| 1. |
- Hegedüs, Luca, et al.
(författare)
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The Prognostic Relevance of PMCA4 Expression in Melanoma : Gender Specificity and Implications for Immune Checkpoint Inhibition
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:6
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Tidskriftsartikel (refereegranskat)abstract
- PMCA4 is a critical regulator of Ca2+ homeostasis in mammalian cells. While its biological and prognostic relevance in several cancer types has already been demonstrated, only preclinical investigations suggested a metastasis suppressor function in melanoma. Therefore, we studied the expression pattern of PMCA4 in human skin, nevus, as well as in primary and metastatic melanoma using immunohistochemistry. Furthermore, we analyzed the prognostic power of PMCA4 mRNA levels in cutaneous melanoma both at the non-metastatic stage as well as after PD-1 blockade in advanced disease. PMCA4 localizes to the plasma membrane in a differentiation dependent manner in human skin and mucosa, while nevus cells showed no plasma membrane staining. In contrast, primary cutaneous, choroidal and conjunctival melanoma cells showed specific plasma membrane localization of PMCA4 with a wide range of intensities. Analyzing the TCGA cohort, PMCA4 mRNA levels showed a gender specific prognostic impact in stage I–III melanoma. Female patients with high transcript levels had a significantly longer progression-free survival. Melanoma cell specific PMCA4 protein expression is associated with anaplasticity in melanoma lung metastasis but had no impact on survival after lung metastasectomy. Importantly, high PMCA4 transcript levels derived from RNA-seq of cutaneous melanoma are associated with significantly longer overall survival after PD-1 blockade. In summary, we demonstrated that human melanoma cells express PMCA4 and PMCA4 transcript levels carry prognostic information in a gender specific manner.
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| 2. |
- Marcell Szasz, A., et al.
(författare)
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Challenging the heterogeneity of disease presentation in malignant melanoma—impact on patient treatment
- 2019
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Ingår i: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 35:1, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- There is an increasing global interest to support research areas that can assist in understanding disease and improving patient care. The National Cancer Institute (NIH) has identified precision medicine-based approaches as key research strategies to expedite advances in cancer research. The Cancer Moonshot program (https://www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative) is the largest cancer program of all time, and has been launched to accelerate cancer research that aims to increase the availability of therapies to more patients and, ultimately, to eradicate cancer. Mass spectrometry-based proteomics has been extensively used to study the molecular mechanisms of cancer, to define molecular subtypes of tumors, to map cancer-associated protein interaction networks and post-translational modifications, and to aid in the development of new therapeutics and new diagnostic and prognostic tests. To establish the basis for our melanoma studies, we have established the Southern Sweden Malignant Melanoma Biobank. Tissues collected over many years have been accurately characterized with respect to the tumor and patient information. The extreme variability displayed in the protein profiles and the detection of missense mutations has confirmed the complexity and heterogeneity of the disease. It is envisaged that the combined analysis of clinical, histological, and proteomic data will provide patients with a more personalized medical treatment. With respect to disease presentation, targeted treatment and medical mass spectrometry analysis and imaging, this overview report will outline and summarize the current achievements and status within malignant melanoma. We present data generated by our cancer research center in Lund, Sweden, where we have built extensive capabilities in biobanking, proteogenomics, and patient treatments over an extensive time period.
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| 3. |
- Moor, Andreas E., et al.
(författare)
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BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer
- 2015
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Ingår i: EBioMedicine. - Ipswich, United States : EBSCO Publishing. - 2352-3964. ; 2:12, s. 1932-1943
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Tidskriftsartikel (refereegranskat)abstract
- BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.
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| 4. |
- Olah, Csilla, et al.
(författare)
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A quantitative polymerase chain reaction based method for molecular subtype classification of urinary bladder cancer—Stromal gene expressions show higher prognostic values than intrinsic tumor genes
- 2022
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 150:5, s. 856-867
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptome-based molecular subtypes of muscle-invasive bladder cancer (MIBC) have been shown to be both prognostic and predictive, but are not used in routine clinical practice. We aimed to develop a feasible, reverse transcription quantitative polymerase chain reaction (RT-qPCR)-based method for molecular subtyping. First, we defined a 68-gene set covering tumor intrinsic (luminal, basal, squamous, neuronal, epithelial-to-mesenchymal, in situ carcinoma) and stromal (immune, extracellular matrix, p53-like) signatures. Then, classifier methods with this 68-gene panel were developed in silico and validated on public data sets with available subtype class information (MD Anderson [MDA], The Cancer Genome Atlas [TCGA], Lund, Consensus). Finally, expression of the selected 68 genes was determined in 104 frozen tissue samples of our MIBC cohort by RT-qPCR using the TaqMan Array Card platform and samples were classified by our newly developed classifiers. The prognostic value of each subtype classification system and molecular signature scores were assessed. We found that the reduced marker set combined with the developed classifiers were able to reproduce the TCGA II, MDA, Lund and Consensus subtype classification systems with an overlap of 79%, 76%, 69% and 64%, respectively. Importantly, we could successfully classify 96% (100/104) of our MIBC samples by using RT-qPCR. Neuronal and luminal subtypes and low stromal gene expressions were associated with poor survival. In conclusion, we developed a robust and feasible method for the molecular subtyping according to the TCGA II, MDA, Lund and Consensus classifications. Our results suggest that stromal signatures have a superior prognostic value compared to tumor intrinsic signatures and therefore underline the importance of tumor-stroma interaction during the progression of MIBC.
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| 5. |
- Olah, Csilla, et al.
(författare)
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Predictive value of molecular subtypes and APOBEC3G for adjuvant chemotherapy in urothelial bladder cancer
- 2023
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 12:5, s. 5222-5232
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Although targeted approaches have become available in second- and third-line settings, platinum-based chemotherapy remains the standard first-line treatment for advanced muscle-invasive bladder cancer (MIBC). Therefore, the prediction of platinum resistance is of utmost clinical importance. Methods: In this study, we established a routine compatible method for the molecular classification of MIBC samples according to various classification systems and applied this method to evaluate the impact of subtypes on survival after adjuvant chemotherapy. This retrospective study included 191 patients with advanced MIBC (pT≥3 or pN+) who underwent radical cystectomy, with or without adjuvant chemotherapy. A 48-gene panel and classifier rule set were established to determine molecular subtypes according to TCGA, MDA, LundTax, and Consensus classifications. Additionally, 12 single platinum-predictive candidate genes were assessed. The results were correlated with patients' clinicopathological and follow-up data and were validated using independent data sets. Results: Our final evaluation of 159 patients demonstrated better survival in the luminal groups for those who received chemotherapy compared with those who did not. In contrast, no such differences were observed in basal subtypes. The use of chemotherapy was associated with better survival in patients with high APOBEC3G expression (p < 0.002). This association was confirmed using an independent data set of patients who received neoadjuvant platinum therapy. Conclusions: The proposed method robustly replicates the most commonly used transcriptome-based subtype classifications from paraffin-embedded tissue samples. The luminal, but not basal, molecular subtypes had the greatest benefit from adjuvant platinum therapy. We identified and validated APOBEC3G as a novel predictive marker for platinum-treated patients.
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| 6. |
- Szász, Marcell, et al.
(författare)
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Cancer heterogeneity determined by functional proteomics
- 2017
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Ingår i: Seminars in Cell and Developmental Biology. - : Elsevier BV. - 1084-9521. ; 64, s. 132-142
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Tidskriftsartikel (refereegranskat)abstract
- Current manuscript gives a synopsis of tumor heterogeneity related to patient samples analyzed by proteomics, protein expression analysis and imaging mass spectrometry.First, we discuss the pathophysiologocal background of cancer biology as a multifactorial and challenging diseases. Disease pathology forms the basis for protein target selection. Therefore, histopathological diagnostics and grading of tumors is highlighted. Pathology is the cornerstone of state-of-the-art diagnostics of tumors today both by establishing dignity and - when needed - describing molecular properties of the cancers. Drug development by the pharmaceutical industry utilizes proteomics studies to pinpoint the most relevant targets. Molecular studies profiling affinity-interactions of the protein(s) with targeted small drug molecules to reach efficacy and optimal patient safety are today requested by the FDA and other agencies for new drug development.An understading of basic mechanisms, controlling drug action and drug binding is central, as a new era of personalized medicine becomes an important milestone solution for the healthcare sector as well as the Pharma and Biotech industry. Development of further diagnostic, prognostic and predictive tests will aid current and future treatment of cancer patients.In the paper we present current status of Proteomics that we believe requires attention in order to collectively advance forward in the fight against cancer, addressing the burning opportunities and challenges.
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