| 1. |
- Ji, Xinyu, et al.
(författare)
-
Epigenetic–smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients
- 2020
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 14:11, s. 2759-2774
-
Tidskriftsartikel (refereegranskat)abstract
- Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30–2.09, P = 4.52 × 10−5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87–1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407TRIM27 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking (37.49LUAD vs 54.79LUSC, P = 1.03 × 10−19) and included a higher proportion of current smokers than LUAD patients (28.24%LUAD vs 34.09%LUSC, P = 0.037). cg05293407TRIM27 was significantly associated with overall survival only in NSCLC patients with medium–high pack-year of smoking (HR = 1.58, 95% CI: 1.26–1.96, P = 5.25 × 10−5). We conclude that cg05293407TRIM27 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.
|
|
| 2. |
- Jobe, Njainday Pulo, et al.
(författare)
-
Reduced WNT5A signaling in melanoma cells favors an amoeboid mode of invasion
- 2021
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 15:7, s. 1835-1848
-
Tidskriftsartikel (refereegranskat)abstract
- Tumor cells invade and spread via either a mesenchymal or an amoeboid mode of migration. Amoeboid tumor cells have a rounded morphology and pronounced RhoA activity. Here, we investigate how WNT5A signaling, a tumor promotor in melanoma, relates to Rho GTPase activity and amoeboid migration. We compared melanoma cells with low (HTB63 cells) and high (WM852 cells) WNT5A expression. HTB63 cells exhibited an amoeboid morphology and had higher RhoA activity but lower invasiveness than WM852 cells in a three-dimensional (3D) collagen matrix. We next explored the relationships between WNT5A, morphology, and invasive behavior. WNT5A knockdown impaired Rho GTPase Cdc42 activity, resulting in reduced invasion of amoeboid and mesenchymal melanoma cells. Interestingly, knockdown of WNT5A or inhibition of its secretion in WM852 cells expressing wild-type BRAF also led to increased RhoA activity via decreased RND3 expression, resulting in predominantly amoeboid morphology. In contrast, such treatments had the opposite effects on RND3 expression and RhoA activity in HTB63 cells expressing the active BRAFV600 mutation. However, treatment of HTB63 cells with a BRAF inhibitor made them respond to WNT5A knockdown in a similar manner as WM852 cells expressing wild-type BRAF. We next found that dual targeting of WNT5A and RhoA more effectively reduced melanoma cell invasion than targeting either protein individually. Taken together, our results suggest that low WNT5A signaling in melanoma cells promotes a rounded amoeboid type of invasion, which quite likely serves as a compensatory response to decreased WNT5A/Cdc42-driven invasion. This phenomenon partially explains the enduring melanoma cell invasion observed after impaired WNT5A signaling and has therapeutic implications. Our results suggest that dual targeting of WNT5A and RhoA signaling is a more effective strategy for controlling the invasion of BRAF wild-type and BRAFV600 mutated melanomas treated with a BRAF inhibitor than targeting either of the proteins individually.
|
|
| 3. |
- Oudenaarden, Clara, et al.
(författare)
-
Upregulated functional gene expression programmes in tumour pericytes mark progression in patients with low-grade glioma
- 2022
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 16:2, s. 405-421
-
Tidskriftsartikel (refereegranskat)abstract
- Pericytes conceivably play important roles in the tumour microenvironment of glioblastoma multiforme (GBM) by allowing for an aberrant vasculature and acting as a component in the perivascular niche that supports glioma stem-like cells. However, a lack of specific markers has hampered in-depth elucidation of the functional contribution of pericytes to GBM. This study provides a comprehensive computational biology approach to annotate pericyte marker genes in the GBM vasculature through integration of data from single-cell RNA-sequencing studies of both mouse and human tissue, as well as bulk tumour- and healthy-tissue gene expression data from patients with GBM. We identified distinct vascular- and immune-related gene expression programmes in tumour pericytes that we assessed for association with GBM characteristics and patient survival. Most compellingly, pericyte gene signatures that were upregulated in tumours compared to normal brain tissue were indicative of progression of low-grade gliomas into high-grade glioma, suggested by a markedly shorter overall survival. Our results underline the functional importance of tumour pericytes in low-grade glioma and may serve as a starting point for efforts for precision targeting of pericytes.
|
|
| 4. |
- Ringborg, Ulrik, et al.
(författare)
-
The Porto European Cancer Research Summit 2021
- 2021
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 15:10, s. 2507-2543
-
Tidskriftsartikel (refereegranskat)abstract
- Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures – namely translational research, clinical/prevention trials and outcomes research – were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.
|
|
| 5. |
- Mitra, Shamik, et al.
(författare)
-
Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma
- 2020
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 14:5, s. 933-950
-
Tidskriftsartikel (refereegranskat)abstract
- The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune-methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand if melanoma tumors resemble other solid tumors in terms of immune-methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune-methylation clusters rather than tumor types. Association of survival outcome with immune cell type-specific methylation differed across tumor and cell types. However, in melanomas immune-cell type-specific methylation was associated with inferior patient survival. Exploration of the immune-methylation patterns in a pan-cancer context suggested that specific immune-microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.
|
|
| 6. |
- Mohapatra, Purusottam, et al.
(författare)
-
Combination therapy targeting the elevated interleukin-6 level reduces invasive migration of BRAF inhibitor-resistant melanoma cells
- 2019
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 13:2, s. 480-494
-
Tidskriftsartikel (refereegranskat)abstract
- The identification of novel antimetastatic therapeutic targets is necessary for improved treatment of patients with acquired BRAF inhibitor-resistant (BRAFi-R) melanoma, in whom metastasis is a major concern. Our present study focused on the identification of such targets to explore novel antimetastatic therapeutic options for BRAFi-R melanoma patients. We confirmed the development of BRAFi resistance in our BRAFi-treated melanoma cell lines by demonstrating reduced sensitivity to BRAF inhibitors, increased ERK1/2 activity and increased WNT5A expression. Here, we demonstrated for the first time that high secretion of interleukin-6 (IL-6) was associated with increased invasive migration of BRAFi-R melanoma cells. This finding could be readily explained by the increased expression of WNT5A in BRAFi-R melanoma cells and the presence of an IL-6/WNT5A positive feedback loop in parental melanoma cells. Surprisingly, however, we found that the IL-6/WNT5A positive feedback loop present in parental melanoma cells was lost during the development of acquired BRAFi resistance, meaning that IL-6 and WNT5A signalling were independent events in BRAFi-R melanoma cells. Despite the absence of an IL-6/WNT5A loop, we found that both an IL-6 blocking antibody and the WNT5A antagonist Box5 alone impaired the elevated invasive migration of BRAFi-R melanoma cells, but combined use of the two was more effective. This impaired invasive migration of BRAFi-R melanoma cells correlated well with the reduction in Cdc42-GTPase activity and alterations of the actin cytoskeleton in these cells. In summary, our novel identification of IL-6 as a key independent promoter of the invasive migration of BRAFi-R melanoma cells stresses that a combination of a blocking IL-6 antibody and administration of the WNT5A antagonist Box5 might be an attractive antimetastatic approach for future treatment of BRAFi-R melanoma patients.
|
|
| 7. |
- Nordgaard, Cathrine, et al.
(författare)
-
Metallopeptidase inhibitor 1 (TIMP-1) promotes receptor tyrosine kinase c-Kit signaling in colorectal cancer
- 2019
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 13:12, s. 2646-2662
-
Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is the third most prevalent cancer worldwide causing an estimated 700 000 deaths annually. Different types of treatment are available for patients with advanced metastatic colorectal cancer, including targeted biological agents, such as cetuximab, a monoclonal antibody that targets EGFR. We have previously reported a study indicating multiple levels of interaction between metallopeptidase inhibitor 1 (TIMP-1) and the epidermal growth factor (EGF) signaling axis, which could explain how TIMP-1 levels can affect the antitumor effects of EGFR inhibitors. We also reported an association between TIMP-1-mediated cell invasive behavior and KRAS status. To gain insight into the molecular mechanisms underlying the effects of TIMP-1 in CRC, we examined by transcriptomics, proteomics, and kinase activity profiling a matched pair of isogenic human CRC isogenic DLD-1 CRC cell clones, bearing either an hemizygous KRAS wild-type allele or KRAS G13D mutant allele, exposed, or not, to TIMP-1. Omics analysis of the two cell lines identified the receptor tyrosine kinase c-Kit, a proto-oncogene that can modulate cell proliferation and invasion in CRC, as a target for TIMP-1. We found that exposure of DLD-1 CRC cells to exogenously added TIMP-1 promoted phosphorylation of c-Kit, indicative of a stimulatory effect of TIMP-1 on the c-Kit signaling axis. In addition, TIMP-1 inhibited c-Kit shedding in CRC cells grown in the presence of exogenous TIMP-1. Given the regulatory roles that c-Kit plays in cell proliferation and migration, and the realization that c-Kit is an important oncogene in CRC, it is likely that some of the biological effects of TIMP-1 overexpression in CRC may be exerted through its effect on c-Kit signaling.
|
|
| 8. |
- Semenas, Julius, et al.
(författare)
-
Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
- 2021
-
Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 15:4, s. 968-986
-
Tidskriftsartikel (refereegranskat)abstract
- Selective ERα modulator, tamoxifen, is well tolerated in a heavily pretreated castration‐resistant prostate cancer (PCa) patient cohort. However, its targeted gene network and whether expression of intratumor ERα due to androgen‐deprivation therapy (ADT) may play a role in PCa progression is unknown. In this study, we examined the inhibitory effect of tamoxifen on castration‐resistant PCa in vitro and in vivo. We found that tamoxifen is a potent compound that induced a high degree of apoptosis and significantly suppressed growth of xenograft tumors in mice, at a degree comparable to ISA‐2011B, an inhibitor of PIP5K1α that acts upstream of PI3K/AKT survival signaling pathway. Moreover, depletion of tumor‐associated macrophages using clodronate in combination with tamoxifen increased inhibitory effect of tamoxifen on aggressive prostate tumors. We showed that both tamoxifen and ISA‐2011B exert their on‐target effects on prostate cancer cells by targeting cyclin D1 and PIP5K1α/AKT network and the interlinked estrogen signaling. Combination treatment using tamoxifen together with ISA‐2011B resulted in tumor regression and had superior inhibitory effect compared with that of tamoxifen or ISA‐2011B alone. We have identified sets of genes that are specifically targeted by tamoxifen, ISA‐2011B or combination of both agents by RNA‐seq. We discovered that alterations in unique gene signatures, in particular estrogen‐related marker genes are associated with poor patient disease‐free survival. We further showed that ERα interacted with PIP5K1α through formation of protein complexes in the nucleus, suggesting a functional link. Our finding is the first to suggest a new therapeutic potential to inhibit or utilize the mechanisms related to ERα, PIP5K1α/AKT network and MMP9/VEGF signaling axis, providing a strategy to treat castration‐resistant ER‐positive subtype of prostate cancer tumors with metastatic potential.
|
|
| 9. |
- Shen, Sipeng, et al.
(författare)
-
A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer
- 2018
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 12:6, s. 913-924
-
Tidskriftsartikel (refereegranskat)abstract
- B-cell translocation gene 2 (BTG2) is a tumour suppressor protein known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early-stage non-small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51-2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28-0.68), which we confirmed with meta-analysis (HR = 0.61, 95% CI 0.54-0.68). The three CpG probes were all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early-stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.
|
|
| 10. |
- Sjöström, Martin, et al.
(författare)
-
Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast-conserving surgery : a long-term follow-up of the SweBCG91-RT randomised trial
- 2020
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 14:11, s. 2713-2726
-
Tidskriftsartikel (refereegranskat)abstract
- Experimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) after adjuvant radiotherapy (RT) in primary breast cancer. HGF, phosphorylated Met (pMet) and phosphorylated Akt (pAkt) were evaluated immunohistochemically on tissue microarrays from 1004 patients in the SweBCG91-RT trial, which randomly assigned patients to breast-conserving therapy, with or without adjuvant RT. HGF was evaluated in the stroma (HGFstr); pMet in the membrane (pMetmem); HGF, pMet and pAkt in the cytoplasm (HGFcyt, pMetcyt, pAktcyt); and pAkt in the nucleus (pAktnuc). The prognostic and treatment predictive effects were evaluated to primary endpoint IBTR as first event during the first 5 years. Patients with tumours expressing low levels of HGFcyt and pMetcyt and high levels of pAktnuc derived a larger benefit from RT [hazard ratio (HR): 0.11 (0.037–0.30), 0.066 (0.016–0.28) and 0.094 (0.028–0.31), respectively] compared to patients with high expression of HGFcyt and pMetcyt, and low pAktnuc [HR: 0.36 (0.19–0.67), 0.35 (0.20–0.64) and 0.47 (0.32–0.71), respectively; interaction analyses: P = 0.052, 0.035 and 0.013, respectively]. These differences remained in multivariable analysis when adjusting for patient age, tumour size, histological grade, St Gallen subtype and systemic treatment (interaction analysis, P-values: 0.085, 0.027, and 0.023, respectively). This study suggests that patients with immunohistochemically low HGFcyt, low pMetcyt and high pAktnuc may derive an increased benefit from RT after breast-conserving surgery concerning the risk of developing IBTR.
|
|
| 11. |
- Therkildsen, Christina, et al.
(författare)
-
Molecular subtype classification of urothelial carcinoma in Lynch syndrome
- 2018
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 12:8, s. 1286-1295
-
Tidskriftsartikel (refereegranskat)abstract
- Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome-associated UC. Thus, Lynch syndrome-associated UCs of the upper urinary tract and the urinary bladder were identified in the Danish hereditary nonpolyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial carcinomas. Whole-genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from patients with Lynch syndrome were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data were analyzed and compared with sporadic bladder cancer. The 41 Lynch syndrome-associated UC developed at a mean age of 61 years with 59% women. mRNA expression profiling and immunostaining classified the majority of the Lynch syndrome-associated UC as urothelial-like tumors with only 20% being genomically unstable, basal/SCC-like, or other subtypes. The subtypes were associated with stage, grade, and microsatellite instability. Comparison to larger datasets revealed that Lynch syndrome-associated UC shares molecular similarities with sporadic UC. In conclusion, transcriptomic and immunohistochemical profiling identifies a predominance of the urothelial-like molecular subtype in Lynch syndrome and reveals that the molecular subtypes of sporadic bladder cancer are relevant also within this hereditary, mismatch-repair defective subset.
|
|
| 12. |
- Zhang, Ruyang, et al.
(författare)
-
SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival : an epigenomic–smoking interaction analysis
- 2019
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 13:5, s. 1235-1248
-
Tidskriftsartikel (refereegranskat)abstract
- Smoking cessation prolongs survival and decreases mortality of patients with non-small-cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome-wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two-stage study design to identify DNA methylation–smoking cessation interactions that affect overall survival for early-stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology-stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation–smoking cessation interaction terms. Interactions with false discovery rate-q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology-specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510 SIPA 1L3 ) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR) interaction = 1.12; 95% confidence interval (CI): 1.07–1.16; P = 4.30 × 10 –7 ]. Further, the effect of smoking cessation on early-stage LUAD survival varied across patients with different methylation levels of cg02268510 SIPA 1L3 . Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34–0.82; P = 4.61 × 10 –3 ) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86–1.70; P = 0.266) of cg02268510 SIPA 1L3 . Moreover, there was an antagonistic interaction between elevated methylation of cg02268510 SIPA 1L3 and smoking cessation (HR interaction = 2.1835; 95% CI: 1.27–3.74; P = 4.46 × 10 −3 ). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510 SIPA 1L3 . The results have implications for not only smoking cessation after diagnosis, but also possible methylation-specific drug targeting.
|
|
| 13. |
- Chen, Jiajin, et al.
(författare)
-
A trans-omics assessment of gene–gene interaction in early-stage NSCLC
- 2023
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 17:1, s. 173-187
-
Tidskriftsartikel (refereegranskat)abstract
- Epigenome-wide gene–gene (G × G) interactions associated with non-small-cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three-step analytic strategy to identify significant and robust G × G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G × G interactions with PBonferroni ≤ 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P ≤ 0.05 in the validation phase. In the second step, we further performed a functional validation for these G × G interactions at the gene expression level by way of a two-phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans-omics analysis, which had significant (P ≤ 0.05) epigenetic cis-regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 (βinteraction = 0.018, P = 1.87 × 10−12), which mapped to RELA × HLA-G (βinteraction = 0.218, P = 8.82 × 10−11) and cg08872738 × cg27077312 (βinteraction = −0.010, P = 1.16 × 10−11), which mapped to TUBA1B × TOMM40 (βinteraction =−0.250, P = 3.83 × 10−10). A trans-omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans-omics G × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.
|
|
| 14. |
- Egelberg, Moa, et al.
(författare)
-
Low levels of WRAP53 predict decreased efficacy of radiotherapy and are prognostic for local recurrence and death from breast cancer : a long-term follow-up of the SweBCG91RT randomized trial
- 2023
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 17:10, s. 2029-2040
-
Tidskriftsartikel (refereegranskat)abstract
- Downregulation of the DNA repair protein WD40-encoding RNA antisense to p53 (WRAP53) has been associated with radiotherapy resistance and reduced cancer survival. The aim of this study was to evaluate WRAP53 protein and RNA levels as prognostic and predictive markers in the SweBCG91RT trial, in which breast cancer patients were randomized for postoperative radiotherapy. Using tissue microarray and microarray-based gene expression, 965 and 759 tumors were assessed for WRAP53 protein and RNA levels, respectively. Correlation with local recurrence and breast cancer-related death was assessed for prognosis, and the interaction between WRAP53 and radiotherapy in relation to local recurrence was assessed for radioresistance prediction. Tumors with low WRAP53 protein levels had a higher subhazard ratio (SHR) for local recurrence [1.76 (95% CI 1.10–2.79)] and breast cancer-related death [1.55 (1.02–2.38)]. Low WRAP53 RNA levels were associated with almost a three-fold decreased effect of radiotherapy in relation to ipsilateral breast tumor recurrence [IBTR; SHR 0.87 (95% CI 0.44–1.72)] compared with high RNA levels [0.33 (0.19–0.55)], with a significant interaction (P = 0.024). In conclusion, low WRAP53 protein is prognostic for local recurrence and breast cancer-related death. Low WRAP53 RNA is a potential marker for radioresistance.
|
|
| 15. |
- Fleischer, Thomas, et al.
(författare)
-
An integrated omics approach highlights how epigenetic events can explain and predict response to neoadjuvant chemotherapy and bevacizumab in breast cancer
- 2024
-
Ingår i: Molecular Oncology. - 1574-7891 .- 1878-0261.
-
Tidskriftsartikel (refereegranskat)abstract
- Treatment with the anti-angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic data in breast cancer patients to predict response to therapy and pinpoint response-related epigenetic events. Fresh-frozen tumor biopsies taken before, during, and after treatment from human epidermal growth factor receptor 2 negative non-metastatic patients receiving neoadjuvant chemotherapy with or without bevacizumab were subjected to molecular profiling. Here, we report that DNA methylation at enhancer CpGs related to cell cycle regulation can predict response to chemotherapy and bevacizumab for the estrogen receptor positive subset of patients (AUC = 0.874), and we validated this observation in an independent patient cohort with a similar treatment regimen (AUC = 0.762). Combining the DNA methylation scores with the scores from a previously published protein signature resulted in a slight increase in the prediction performance (AUC = 0.784). We also show that tumors receiving the combination treatment underwent more extensive epigenetic alterations. Finally, we performed an integrative expression–methylation quantitative trait loci analysis on alterations in DNA methylation and gene expression levels, showing that the epigenetic alterations that occur during treatment are different between responders and non-responders and that these differences may be explained by the proliferation–epithelial-to-mesenchymal transition axis through the activity of grainyhead like transcription factor 2. Using tumor purity computed from copy number data, we developed a method for estimating cancer cell-specific methylation to confirm that the association to response reflects DNA methylation in cancer cells. Taken together, these results support the potential for clinical benefit of the addition of bevacizumab to chemotherapy when administered to the correct patients.
|
|
| 16. |
- Flodbring Larsson, Per, et al.
(författare)
-
FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer
- 2022
-
Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261.
-
Tidskriftsartikel (refereegranskat)abstract
- Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FcγRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FcγRIIIa expression, suggesting that FcγRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FcγRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FcγRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FcγRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FcγRIIIa protein expression. Similarly, inhibition of PIP5K1α decreased FcγRIIIa expression in PCa cells. FcγRIIIa physically interacted with PIP5K1α and AR via formation of protein-protein complexes, suggesting that FcγRIIIa is functionally associated with AR and PIP5K1α in PCa cells. Our study identified FcγRIIIa as an important factor in promoting PCa growth and invasion. Further, the elevated activation of FcγRIII and AR and PIP5K1α pathways may cooperatively promote PCa growth and invasion. Thus, FcγRIIIa may serve as a potential new target for improved treatment of metastatic and castration-resistant PCa.
|
|
| 17. |
- Ji, Xinyu, et al.
(författare)
-
Epigenome-wide three-way interaction study identifies a complex pattern between TRIM27, KIAA0226, and smoking associated with overall survival of early-stage NSCLC
- 2022
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 16:3, s. 717-731
-
Tidskriftsartikel (refereegranskat)abstract
- The interaction between DNA methylation of tripartite motif containing 27 (cg05293407TRIM27) and smoking has previously been identified to reveal histologically heterogeneous effects of TRIM27 DNA methylation on early-stage non-small-cell lung cancer (NSCLC) survival. However, to understand the complex mechanisms underlying NSCLC progression, we searched three-way interactions. A two-phase study was adopted to identify three-way interactions in the form of pack-year of smoking (number of cigarettes smoked per day × number of years smoked) × cg05293407TRIM27 × epigenome-wide DNA methylation CpG probe. Two CpG probes were identified with FDR-q ≤ 0.05 in the discovery phase and P ≤ 0.05 in the validation phase: cg00060500KIAA0226 and cg17479956EXT2. Compared to a prediction model with only clinical information, the model added 42 significant three-way interactions using a looser criterion (discovery: FDR-q ≤ 0.10, validation: P ≤ 0.05) had substantially improved the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model for both 3-year and 5-year survival. Our research identified the complex interaction effects among multiple environment and epigenetic factors, and provided therapeutic target for NSCLC patients.
|
|
| 18. |
- Modvig, Signe, et al.
(författare)
-
High CD34 surface expression in BCP-ALL predicts poor induction therapy response and is associated with altered expression of genes related to cell migration and adhesion
- 2022
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 16:10, s. 2015-2030
-
Tidskriftsartikel (refereegranskat)abstract
- Minimal residual disease (MRD) constitutes the most important prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Flow cytometry is widely used in MRD assessment, yet little is known regarding the effect of different immunophenotypic subsets on outcome. In this study of 200 BCP-ALL patients, we found that a CD34-positive, CD38 dim-positive, nTdT dim-positive immunophenotype on the leukemic blasts was associated with poor induction therapy response and predicted an MRD level at the end of induction therapy (EOI) of ≥ 0.001. CD34 expression was strongly and positively associated with EOI MRD, whereas CD34-negative patients had a low relapse risk. Further, CD34 expression increased from diagnosis to relapse. CD34 is a stemness-associated cell-surface molecule, possibly involved in cell adhesion/migration or survival. Accordingly, genes associated with stemness were overrepresented among the most upregulated genes in CD34-positive leukemias, and protein–protein interaction networks showed an overrepresentation of genes associated with cell migration, cell adhesion, and negative regulation of apoptosis. The present work is the first to demonstrate a CD34-negative immunophenotype as a good prognostic factor in ALL, whereas high CD34 expression is associated with poor therapy response and an altered gene expression profile reminiscent of migrating cancer stem-like cells.
|
|
| 19. |
- Abou-Zeid, Nancy, et al.
(författare)
-
Towards a cancer mission in Horizon Europe: recommendations
- 2020
-
Ingår i: Molecular Oncology. - : Wiley Open Access. - 1878-0261 .- 1574-7891. ; 14:8, s. 1589-1615
-
Tidskriftsartikel (refereegranskat)abstract
- A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research–care–prevention continuum has the potential to achieve in 2030 a 10-year cancer-specific survival for 75% of patients diagnosed in European Union (EU) member states with a well-developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high-quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science-driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC-like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long-term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans-border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence-based advice.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
- Garcia-Gomez, Pedro, et al.
(författare)
-
NOX4 regulates TGF beta-induced proliferation and self-renewal in glioblastoma stem cells
- 2022
-
Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 16:9, s. 1891-1912
-
Tidskriftsartikel (refereegranskat)abstract
- Y Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulation - glioblastoma stem cells (GSCs) - that has been held responsible for glioblastoma initiation, cell invasion, proliferation, relapse and resistance to chemo- and radiotherapy. Targeted therapies against GSCs are crucial, as is understanding the molecular mechanisms that govern the GSCs. Transforming growth factor beta (TGF beta) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGF beta in a transcriptomic analysis of two different patient-derived GSCs, we found NADPH oxidase 4 (NOX4) as one of the top upregulated genes. Interestingly, when patient tissues were analysed, NOX4 expression was found to be higher in GSCs versus differentiated cells. A functional analysis of the role of NOX4 downstream of TGF beta in several patient-derived GSCs showed that TGF beta does indeed induce NOX4 expression and increases ROS production in a NOX4-dependent manner. NOX4 downstream of TGF beta regulates GSC proliferation, and NOX4 expression is necessary for TGF beta-induced expression of stem cell markers and of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which in turn controls the cell's antioxidant and metabolic responses. Interestingly, overexpression of NOX4 recapitulates the effects induced by TGF beta in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.
|
|
| 25. |
- Gulley, James L., et al.
(författare)
-
Dual inhibition of TGF-beta and PD-L1 : a novel approach to cancer treatment
- 2022
-
Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 16:11, s. 2117-2134
-
Forskningsöversikt (refereegranskat)abstract
- Transforming growth factor-beta (TGF-beta) and programmed death-ligand 1 (PD-L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF-beta signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial-to-mesenchymal transition, and angiogenesis. Meanwhile, PD-L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti-PD-L1 therapies have been approved for the treatment of various cancers, but TGF-beta signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF-beta and PD-L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual-targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual-targeting agent is bintrafusp alfa. This drug is a first-in-class bifunctional fusion protein that consists of the extracellular domain of the TGF-beta RII receptor (a TGF-beta 'trap') fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD-L1. Given the immunosuppressive effects of the TGF-beta and PD-L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.
|
|
| 26. |
- Hühn, Daniela, et al.
(författare)
-
Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells
- 2021
-
Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 16:1, s. 148-165
-
Tidskriftsartikel (refereegranskat)abstract
- Among others, expression levels of programmed cell death 1 ligand 1 (PD-L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD-L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD-L1 downregulators. In addition, we identified that PD-L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ER alpha) inhibition triggers a broad immunosuppressive program in ER-positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen-presenting machinery. Accordingly, estrogen-deprived MCF7 cells are resistant to T-cell-mediated cell killing, in a manner that is independent of PD-L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER-positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion.
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
- Tanabe, Ryo, et al.
(författare)
-
PRRX1 induced by BMP signaling decreases tumorigenesis by epigenetically regulating glioma-initiating cell properties via DNA methyltransferase 3A
- 2022
-
Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 16:1, s. 269-288
-
Tidskriftsartikel (refereegranskat)abstract
- Glioma-initiating cells (GICs), a major source of glioblastoma recurrence, are characterized by the expression of neural stem cell markers and the ability to grow by forming nonadherent spheres under serum-free conditions. Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta family, induce differentiation of GICs and suppress their tumorigenicity. However, the mechanisms underlying the BMP-induced loss of GIC stemness have not been fully elucidated. Here, we show that paired related homeobox 1 (PRRX1) induced by BMPs decreases the CD133-positive GIC population and inhibits tumorigenic activity of GICs in vivo. Of the two splice isoforms of PRRX1, the longer isoform, pmx-1b, but not the shorter isoform, pmx-1a, induces GIC differentiation. Upon BMP stimulation, pmx-1b interacts with the DNA methyltransferase DNMT3A and induces promoter methylation of the PROM1 gene encoding CD133. Silencing DNMT3A maintains PROM1 expression and increases the CD133-positive GIC population. Thus, pmx-1b promotes loss of stem cell-like properties of GICs through region-specific epigenetic regulation of CD133 expression by recruiting DNMT3A, which is associated with decreased tumorigenicity of GICs.
|
|
| 31. |
- Thysell, Elin, et al.
(författare)
-
Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C
- 2022
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 16:4, s. 846-859
-
Tidskriftsartikel (refereegranskat)abstract
- To improve treatment of metastatic prostate cancer, the biology of metastases needs to be understood. We recently described three subtypes of prostate cancer bone metastases (MetA-C), based on differential gene expression. The aim of this study was to verify the clinical relevance of these subtypes and to explore their biology and relations to genetic drivers. Freshly-frozen metastasis samples were obtained as hormone-naive (n = 17), short-term castrated (n = 21), or castration-resistant (n = 65) from a total of 67 patients. Previously published sequencing data from 573 metastasis samples were also analyzed. Through transcriptome profiling and sample classification based on a set of predefined MetA-C-differentiating genes, we found that most metastases were heterogeneous for the MetA-C subtypes. Overall, MetA was the most common subtype, while MetB was significantly enriched in castration-resistant samples and in liver metastases, and consistently associated with poor prognosis. By gene set enrichment analysis, the phenotype of MetA was described by high androgen response, protein secretion and adipogenesis, MetB by high cell cycle activity and DNA repair, and MetC by epithelial-to-mesenchymal transition and inflammation. The MetB subtype demonstrated single nucleotide variants of RB transcriptional corepressor 1 (RB1) and loss of 21 genes at chromosome 13, including RB1, but provided independent prognostic value to those genetic aberrations. In conclusion, a distinct set of gene transcripts can be used to classify prostate cancer metastases into the subtypes MetA-C. The MetA-C subtypes show diverse biology, organ tropism, and prognosis. The MetA-C classification may be used independently, or in combination with genetic markers, primarily to identify MetB patients in need of complementary therapy to conventional androgen receptor-targeting treatments.
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
- Delaunay, Tiphaine, et al.
(författare)
-
Aberrant expression of kallikrein-related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion
- 2017
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 11:10, s. 1330-1347
-
Tidskriftsartikel (refereegranskat)abstract
- Members of the tissue kallikrein-related peptidase (KLK) family not only regulate several important physiological functions, but aberrant expression has also been associated with various malignancies. Clinically, KLKs have been suggested as promising biomarkers for diagnosis and prognosis in many types of cancer. As of yet, expression of KLKs and their role in skin cancers are, however, poorly addressed. Malignant melanoma is an aggressive disease associated with poor prognosis. Hence, diagnostic biomarkers to monitor melanoma progression are needed. Herein, we demonstrate that although mRNA of several KLKs are aberrantly expressed in melanoma cell lines, only the KLK7 protein is highly secreted in vitro. In line with these findings, ectopic expression of KLK7 in human melanomas and its absence in benign nevi were demonstrated by immunohistochemistry in vivo. Interestingly, overexpression of KLK7 induced a significant reduction in melanoma cell proliferation and colony formation. Moreover, KLK7 overexpression triggered an increase in cell motility and invasion associated with decreased expression of E-cadherin and an upregulation of MCAM/CD146. Our results demonstrate, for the first time, that aberrant KLK7 expression leads to a switch from proliferative to invasive phenotype, suggesting a potential role of KLK7 in melanoma progression. Thus, we hypothesize that KLK7 may represent a potential biomarker for melanoma progression.
|
|
| 39. |
|
|
| 40. |
- Dillner, J
(författare)
-
Early detection and prevention
- 2019
-
Ingår i: Molecular oncology. - : Wiley. - 1878-0261 .- 1574-7891. ; 13:3, s. 591-598
-
Tidskriftsartikel (refereegranskat)
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
- Franzen, Bo, et al.
(författare)
-
A fine-needle aspiration-based protein signature discriminates benign from malignant breast lesions
- 2018
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 12:9, s. 1415-1428
-
Tidskriftsartikel (refereegranskat)abstract
- There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and to follow-up personalized cancer therapy. Fine-needle aspiration (FNA) biopsy provides ready access to relevant tissues; however, the minute sample amounts require sensitive multiplex molecular analysis to achieve clinical utility. We have applied proximity extension assays (PEA) and NanoString (NS) technology for analyses of proteins and of RNA, respectively, in FNA samples. Using samples from patients with breast cancer (BC, n=25) or benign lesions (n=33), we demonstrate that these FNA-based molecular analyses (a) can offer high sensitivity and reproducibility, (b) may provide correct diagnosis in shorter time and at a lower cost than current practice, (c) correlate with results from routine analysis (i.e., benchmarking against immunohistochemistry tests for ER, PR, HER2, and Ki67), and (d) may also help identify new markers related to immunotherapy. A specific 11-protein signature, including FGF binding protein 1, decorin, and furin, distinguished all cancer patient samples from all benign lesions in our main cohort and in smaller replication cohort. Due to the minimally traumatic sampling and rich molecular information, this combined proteomics and transcriptomic methodology is promising for diagnostics and evaluation of treatment efficacy in BC.
|
|
| 44. |
- Franzen, Bo, et al.
(författare)
-
Protein profiling of fine-needle aspirates reveals subtype-associated immune signatures and involvement of chemokines in breast cancer
- 2019
-
Ingår i: Molecular Oncology. - : WILEY. - 1574-7891 .- 1878-0261. ; 13:2, s. 376-391
-
Tidskriftsartikel (refereegranskat)abstract
- There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and for follow-up of personalized cancer therapy, including immunotherapy. Fine-needle aspiration (FNA) biopsy provides ready access to relevant tissue samples; however, the minute amounts of sample require sensitive multiplex molecular analysis to be of clinical biomarker utility. We have applied proximity extension assays (PEA) to analyze 167 proteins in FNA samples from patients with breast cancer (BC; n = 25) and benign lesions (n = 32). We demonstrate that the FNA BC samples could be divided into two main clusters, characterized by differences in expression levels of the estrogen receptor (ER) and the proliferation marker Ki67. This clustering corresponded to some extent to established BC subtypes. Our analysis also revealed several proteins whose expression levels differed between BC and benign lesions (e.g., CA9, GZMB, IL-6, VEGFA, CXCL11, PDL1, and PCD1), as well as several chemokines correlating with ER and Ki67 status (e.g., CCL4, CCL8, CCL20, CXCL8, CXCL9, and CXCL17). Finally, we also identified three signatures that could predict Ki67 status, ER status, and tumor grade, respectively, based on a small subset of proteins, which was dominated by chemokines. To our knowledge, expression profiles of CCL13 in benign lesions and BC have not previously been described but were shown herein to correlate with proliferation (P = 0.00095), suggesting a role in advanced BC. Given the broad functional range of the proteins analyzed, immune-related proteins were overrepresented among the observed alterations. Our pilot study supports the emerging role of chemokines in BC progression. Due to the minimally traumatic sampling and clinically important molecular information for therapeutic decisions, this methodology is promising for future immunoscoring and monitoring of treatment efficacy in BC.
|
|
| 45. |
|
|
| 46. |
- Ibarra, Cristian, et al.
(författare)
-
BCG-induced cytokine release in bladder cancer cells is regulated by Ca2+ signaling
- 2019
-
Ingår i: Molecular Oncology. - : WILEY. - 1574-7891 .- 1878-0261. ; 13:2, s. 202-211
-
Tidskriftsartikel (refereegranskat)abstract
- Bacillus Calmette-Guerin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.
|
|
| 47. |
- Jacobsson, Hanna, et al.
(författare)
-
Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways
- 2019
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 13:8, s. 1693-1705
-
Tidskriftsartikel (refereegranskat)abstract
- It is well known that tumour cells are dependent on communication with the tumour microenvironment. Previously, it has been shown that hypoxia (HX) induces pronounced, diverse and direct effects on cancer stem cell (CSC) qualities in different breast cancer subtypes. Here, we describe the mechanism by which HX-induced secretion influences the spreading of CSCs. Conditioned media (CM) from estrogen receptor (ER)-α-positive hypoxic breast cancer cell cultures increased the fraction of CSCs compared to normal growth conditions, as determined using sets of CSC assays and model systems. In contrast, media from ERα-negative hypoxic cell cultures instead decreased this key subpopulation of cancer cells. Further, there was a striking overrepresentation of JAK-STAT-associated cytokines in both the ERα-positive and ERα-negative linked hypoxic responses as determined by a protein screen of the CM. JAK-STAT inhibitors and knockdown experiments further supported the hypothesis that this pathway is critical for the CSC-activating and CSC-inactivating effects induced by hypoxic secretion. We also observed that the interleukin-6-JAK2-STAT3 axis was specifically central for the ERα-negative hypoxic behaviour. Our results underline the importance of considering breast cancer subtypes in treatments targeting JAK-STAT or HX-associated processes and indicate that HX is not only a confined tumour biological event, but also influences key tumour properties in widespread normoxic microenvironments. © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
|
|
| 48. |
- Jamin, Soazik P., et al.
(författare)
-
Combined RNA/tissue profiling identifies novel Cancer/testis genes
- 2021
-
Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 15:11, s. 3003-3023
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer/Testis (CT) genes are induced in germ cells, repressed in somatic cells, and derepressed in somatic tumors, where these genes can contribute to cancer progression. CT gene identification requires data obtained using standardized protocols and technologies. This is a challenge because data for germ cells, gonads, normal somatic tissues, and a wide range of cancer samples stem from multiple sources and were generated over substantial periods of time. We carried out a GeneChip-based RNA profiling analysis using our own data for testis and enriched germ cells, data for somatic cancers from the Expression Project for Oncology, and data for normal somatic tissues from the Gene Omnibus Repository. We identified 478 candidate loci that include known CT genes, numerous genes associated with oncogenic processes, and novel candidates that are not referenced in the Cancer/Testis Database (). We complemented RNA expression data at the protein level for SPESP1, GALNTL5, PDCL2, and C11orf42 using cancer tissue microarrays covering malignant tumors of breast, uterus, thyroid, and kidney, as well as published RNA profiling and immunohistochemical data provided by the Human Protein Atlas (). We report that combined RNA/tissue profiling identifies novel CT genes that may be of clinical interest as therapeutical targets or biomarkers. Our findings also highlight the challenges of detecting truly germ cell-specific mRNAs and the proteins they encode in highly heterogenous testicular, somatic, and tumor tissues.
|
|
| 49. |
- Jönsson, Bengt, et al.
(författare)
-
Mission-oriented transnational cancer research - health economics
- 2019
-
Ingår i: Molecular Oncology. - : Wiley Open Access. - 1878-0261 .- 1574-7891. ; 13:3, s. 636-647
-
Tidskriftsartikel (refereegranskat)abstract
- Health economics is an integrated aspect of all phases of mission‐oriented translational cancer research and should be considered an intrinsic component of any study aimed at improving outcomes for patients and intervention costs. Information about value and value for money of new options for prevention and treatment is needed for decisions about their adoption and use by healthcare systems.
|
|
| 50. |
|
|
