Neoplastic–Stromal Cell Cross-talk Regulates Matrisome Expression in Pancreatic Cancer
| Autor: | Andrew S. Liss, Thomas Hank, Peter Bronsert, Akifumi Nakagawa, Martin L. Biniossek, Tobias Keck, Kim C. Honselmann, Annie Li, Christian S Monsalve, David J Birnbaum, Eric Tai, Sebastian K.S. Begg, Keith D. Lillemoe, Oliver Schilling, Himanshu Sharma, François Bertucci, Matteo Ligorio, Pascal Finetti, Ulrich F. Wellner, Carlos Fernandez-del Castillo, Andrew L. Warshaw, Mari Mino-Kenudson, Cristina R. Ferrone, Daniel Birnbaum, Matthew A Goldsworthy, David T. Ting |
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| Přispěvatelé: | Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Pittsburgh, Pittsburgh, PA, USA, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Freiburg [Freiburg] |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Stromal cell [SDV.CAN]Life Sciences [q-bio]/Cancer Cell Communication Biology Extracellular matrix 03 medical and health sciences Mice 0302 clinical medicine Cancer-Associated Fibroblasts Pancreatic cancer Cell Line Tumor Gene expression Acetamides medicine Tumor Microenvironment Animals Humans Molecular Biology ComputingMilieux_MISCELLANEOUS Cell Proliferation Extracellular Matrix Proteins Cancer Azepines medicine.disease Xenograft Model Antitumor Assays In vitro Chromatin Gene Expression Regulation Neoplastic Pancreatic Neoplasms 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research Collagen Carcinoma Pancreatic Ductal |
| Zdroj: | Molecular Cancer Research Molecular Cancer Research, 2020, 18 (12), pp.1889-1902. ⟨10.1158/1541-7786.mcr-20-0439⟩ |
| ISSN: | 1541-7786 1557-3125 |
| DOI: | 10.1158/1541-7786.mcr-20-0439⟩ |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer–stroma communication. In this study, we interrogated the contribution of the BET family of chromatin adaptors to the cross-talk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small-molecule inhibitor of BET proteins, resulted in broad changes in the expression of genes encoding components of the extracellular matrix (matrisome) in both cancer and stromal cells. Remarkably, more than half of matrisome genes were expressed by cancer cells. In vitro cocultures of PDAC cells and cancer-associated fibroblasts (CAF) demonstrated that matrisome expression was regulated by BET-dependent cancer–CAF cross-talk. Disrupting this cross-talk in vivo resulted in diminished growth of orthotopic patient-derived xenograft tumors, reduced proliferation of cancer cells, and changes in collagen structure consistent with that of patients who experienced better survival. Examination of matrisome gene expression in publicly available data sets of 573 PDAC tumors identified a 65-gene signature that was able to distinguish long- and short-term PDAC survivors. Importantly, the expression of genes predictive of short-term survival was diminished in the cancer cells of orthotopic xenograft tumors of mice treated with CPI203. Taken together, these results demonstrate that inhibiting the activity BET proteins results in transcriptional and structural differences in the matrisome are associated with better patient survival. Implications: These studies highlight the biological relevance of the matrisome program in PDAC and suggest targeting of epigenetically driven tumor–stroma cross-talk as a potential therapeutic avenue. |
| Databáze: | OpenAIRE |
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