| 1. |
- Bartoschek, Michael
(författare)
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Exploring functional subsets of cancer-associated fibroblasts
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The tumor microenvironment consists of several interacting cell types. Cancer research focssed mainly on the malignant cell in the past. The importance of the tumor microenvironment is increasingly appreciated, as endothelial cells and immune cells were identified as targets for anti-tumor therapy. Targeted therapy against cancer-associated fibroblasts (CAFs) are not in clinical use for the treatment of carcinomas, even though CAFs are involved in many tumor-supporting processes. CAFs are mesenchymal stromal cells and generate and modulate the extracellular matrix (ECM), which provides physical stability to the growing tumor. CAFs can alter cell-to-cell communication within the tumor microenvironment and thereby influence the immune reaction to cancer cells, the response to cancer therapy and the tumor metabolism.Breast cancer is the most common malignant disease and second most common reason for cancer-related death in women. Despite advancements in the treatment of breast cancer, some aggressive forms remain hard to treat.In the first paper we investigated the effect of complement oligomeric matrix protein (COMP) on breast cancer. Epithelial COMP expression is associated with reduced survival in breast cancer patients.We showed that COMP resolves endoplasmic reticulum stress and deregulates the cell metabolism, causing increased growth and metastasis in vivo. We propose COMP expression as a potential prognostic marker in breast cancer.In the second part of the thesis we analyzed the importance of platelet-derived growth factor (PDGF) signaling in solid tumors in general, and the effect of PDGF-CC signaling in breast cancer in particular. We showed that PDGF-CC signaling to CAFs and the subsequent release of CAF-derived stanniocalcin 1, hepatocyte growth factor, and insulin growth factor binding protein 3 maintain a basal-like phenotype in breast cancer. Genetic and pharmacologic disruption of this commuication loop resulted in conversion of a hormone receptor-negative into a hormone receptor-positive state, causing enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that the breast cancer subtype is in part under the control of the tumor microenvironment.CAFs have many different functions in the tumor microenvironment and different origins for CAFs have been suggested. In the last paper we used single-cell RNA-sequencing of 786 mesenchymal cells derived from tumors of the MMTV-PyMT mouse model of breast cancer, to identify subclasses of CAFs in an unbiased approach. We detected and confirmed the existence of four subclasses that potentially derive from three different origins. Based on differential gene expression analysis we assigned functional properties to each CAF subgroup. Gene profiles of the main CAF subgroups held independent prognostic capability in large clinical cohorts. We showed that an in depth investigation of cellular constituents of the tumor microenvironment with increased resolution, can reveal a higher order of cellular organization in malignant disease.
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| 2. |
- Bartoschek, Michael, et al.
(författare)
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PDGF family function and prognostic value in tumor biology
- 2018
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 503:2, s. 984-990
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Tidskriftsartikel (refereegranskat)abstract
- The development and progression of a tumor depends on the close interaction of malignant cells and the supportive and suppressive tumor microenvironment. Paracrine signaling enables tumor cells to shape the surrounding tissue in order to decrease recognition by the immune system, attract blood vessels to fuel growth, change metabolic programs, and induce wound healing programs. In this study, we investigate the role of the platelet-derived growth factor (PDGF) family members PDGFA, PDGFB, PDGFC and PDGFD and their cognate tyrosine kinase receptors PDGFRA and PDGFRB, using publicly available data from The Cancer Genome Atlas and the Human Protein Atlas. Large scale analysis of expression correlation in RNA sequencing data from 7616 samples derived from 16 tumor types, revealed conserved functional programs in PDGF signaling in the majority of solid tumor types. Besides the well-known effects of PDGF signaling in mesenchymal cells, our analyses revealed a potential role of PDGF signaling in the composition of the immune microenvironment. We furthermore derived gene signatures with increased prognostic value for each PDGF family member. This study emphasizes the potential to impinge on specific paracrine signaling events to interfere with the crosstalk between malignant cells and their microenvironment.
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| 3. |
- Bartoschek, Michael, et al.
(författare)
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Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, although their origin and roles in shaping disease initiation, progression and treatment response remain unclear due to significant heterogeneity. Here, following a negative selection strategy combined with single-cell RNA sequencing of 768 transcriptomes of mesenchymal cells from a genetically engineered mouse model of breast cancer, we define three distinct subpopulations of CAFs. Validation at the transcriptional and protein level in several experimental models of cancer and human tumors reveal spatial separation of the CAF subclasses attributable to different origins, including the peri-vascular niche, the mammary fat pad and the transformed epithelium. Gene profiles for each CAF subtype correlate to distinctive functional programs and hold independent prognostic capability in clinical cohorts by association to metastatic disease. In conclusion, the improved resolution of the widely defined CAF population opens the possibility for biomarker-driven development of drugs for precision targeting of CAFs.
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| 4. |
- Bocci, Matteo, et al.
(författare)
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Activin receptor-like kinase 1 is associated with immune cell infiltration and regulates CLEC14A transcription in cancer
- 2019
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Ingår i: Angiogenesis. - : Springer Science and Business Media LLC. - 0969-6970 .- 1573-7209. ; 22:1, s. 117-131
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells sustain their metabolic needs through nutrients and oxygen supplied by the bloodstream. The requirement for tumor angiogenesis has been therapeutically exploited in the clinical setting mainly by means of inhibition of the vascular endothelial growth factor family of ligands and receptors. Despite promising results in preclinical models, the benefits for patients proved to be limited. Inadequate efficacy similarly halted the development of agents impinging on the activity of the activin receptor-like kinase (ALK)1, a member of the transforming growth factor-β superfamily. Notwithstanding its characterization as an endothelial cell marker, the full spectrum of biological processes associated with ALK1 is essentially unexplored. Here, we present data revealing the genetic network associated with ACVRL1 (the gene encoding for ALK1) expression in human cancer tissues. Computational analysis unveiled a hitherto unknown role for ACVRL1 in relation to genes modulating the functionality of the immune cell compartment. Moreover, we generated a signature of 8 genes co-expressed with ACVRL1 across different tumor types and characterized the c-type lectin domain containing protein (CLEC)14A as a potential downstream target of ACVRL1. Considering the lack of reagents for ALK1 detection that has hampered the field to date, our work provides the opportunity to validate the 8-gene signature and CLEC14A as biomarkers for ALK1 activity. Ultimately, this may help revisit the clinical development of already existing ALK1-blocking compounds as precision medicines for cancer.
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| 5. |
- Cunha, Sara I., et al.
(författare)
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Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer.
- 2015
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Ingår i: Cancer Research. - 1538-7445 .- 0008-5472. ; 75:12, s. 2445-2456
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Tidskriftsartikel (refereegranskat)abstract
- Exploration of new strategies for the prevention of breast cancer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested case-control study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer. Cancer Res; 75(12); 2445-56. ©2015 AACR.
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| 6. |
- Escudero-Esparza, Astrid, et al.
(författare)
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Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:47, s. 76920-76933
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Tidskriftsartikel (refereegranskat)abstract
- Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane-bound complement inhibitor suggested to act as a putative tumor suppressor gene, since allelic loss of this region encompassing 8p23 including CSMD1 characterizes various malignancies. Here, we assessed the role of CSMD1 as a tumor suppressor gene in the development of breast cancer in vitro and in vivo. We found that human breast tumor tissues expressed CSMD1 at lower levels compared to that in normal mammary tissues. The decreased expression of CSMD1 was linked to a shorter overall survival of breast cancer patients. We also revealed that expression of CSMD1 in human breast cancer cells BT-20 and MDA-MB-231 significantly inhibited their malignant phenotypes, including migration, adhesion and invasion. Conversely, stable silencing of CSMD1 expression in T47D cells enhanced cancer cell migratory, adherent and clonogenic abilities. Moreover, expression of CSMD1 in the highly invasive MDA-MB-231 cells diminished their signaling potential as well as their stem cell-like properties as assessed by measurement of aldehyde dehydrogenase activity. In a xenograft model, expression of CSMD1 blocked the ability of cancer cells to metastasize to secondary sites in vivo, likely via inhibiting local invasion but not the extravasation into distant tissues. Taken together, these findings demonstrate the role of CSMD1 as a tumor suppressor gene in breast cancer.
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| 7. |
- Papadakos, Konstantinos S., et al.
(författare)
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Cartilage Oligomeric Matrix Protein initiates cancer stem cells through activation of Jagged1-Notch3 signaling
- 2019
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Ingår i: Matrix Biology. - : Elsevier BV. - 0945-053X. ; 81, s. 107-121
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Tidskriftsartikel (refereegranskat)abstract
- Cancer stem cell populations are important for the initiation, progression and metastasis of tumors. The mechanisms governing cancer stem cell control are only partially understood, but activation of the Notch3 pathway plays a crucial role in the maintenance of breast cancer stem cells. Expression of Cartilage Oligomeric Matrix Protein (COMP) in breast cancer cells is correlated with poor survival and higher recurrence rates in patients. In this study, we provide in vivo and in vitro evidence that COMP expression increases the proportion of cancer stem cells in breast cancer. Thus, MDA-MB-231 and BT-20 cells expressing COMP formed larger tumorspheres in vivo and in vitro and displayed higher ALDH-activity than cells lacking COMP. Additionally, BT-20 COMP-expressing cells displayed higher expression of CD133 compared with the control cells. Furthermore, among the different Notch receptors, Notch3 is specifically activated in COMP-expressing cells. Mechanistically, activation of Notch3 is mediated by secreted, polymeric COMP, which interacts with both Notch3 and its ligand Jagged1, bridging the receptor and ligand together, enhancing Notch3-specific signaling. COMP-dependent Notch3 activation also leads to cross-talk with β-Catenin and AKT pathways. Using the model of MMTV-PyMT mouse breast tumorigenesis, we observed a decrease in the size of tumors and the amount of cancer stem cells as well as reduced Notch3 activation, in COMP knockout mice in comparison to wild type mice. In conclusion, we reveal a novel molecular mechanism whereby COMP regulates the cancer stem cell population through increasing the interaction between Notch3 and Jagged1, leading to increased activation of Notch3 signaling.
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| 8. |
- Quandt, Jasmin, et al.
(författare)
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Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses
- 2018
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Ingår i: OncoImmunology. - 2162-4011. ; 7:12
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Tidskriftsartikel (refereegranskat)abstract
- Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28–35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.
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| 9. |
- Roswall, Pernilla, et al.
(författare)
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Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling
- 2018
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 24, s. 463-473
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Tidskriftsartikel (refereegranskat)abstract
- Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal-like subtype is under microenvironmental control and is therapeutically actionable.
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