Neoplastic–stromal cell cross-talk regulates matrisome expression in pancreatic cancer

Kim C. Honselmann, Pascal Finetti, David J. Birnbaum, Christian S. Monsalve, Ulrich F. Wellner, Sebastian K.S. Begg, Akifumi Nakagawa, Thomas Hank, Annie Li, Mathew A. Goldsworthy, Himanshu Sharma, François Bertucci, Daniel Birnbaum, Eric Tai, Matteo Ligorio, David T. Ting, Oliver Schilling, Martin L. Biniossek, Peter Bronsert, Cristina R. FerroneTobias Keck, Mari Mino-Kenudson, Keith D. Lillemoe, Andrew L. Warshaw, Carlos Fernandez-Del Castillo, Andrew S. Liss

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1889-1902
Number of pages14
JournalMolecular Cancer Research
Volume18
Issue number12
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Neoplastic–stromal cell cross-talk regulates matrisome expression in pancreatic cancer'. Together they form a unique fingerprint.

Cite this