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Kim C. Honselmann*1, Mari Mino-Kenudson2, Akifumi Nakagawa1, Keith D. Lillemoe1, Carlos Fernandez-Del Castillo1, Andrew L. Warshaw1, Andrew S. Liss1
1Surgery, Massachusetts General Hospital, Boston, MA; 2Pathology, Massachusets General Hospital, Boston, MA

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic stroma, composed of abundant fibrosis and cancer-associated fibroblasts (CAFs). Recent work has revealed that the BET family of epigenetic regulators plays a key role in the growth of both PDAC cells and CAFs in tumors. However, the extent and mechanisms by which BET regulates the tumor microenvironment are unclear. The aims of this study are to determine whether BET inhibition structurally alters the extracellular matrix (ECM) and to define the mechanisms by which BET proteins exert these effects.
Methods: Mice bearing heterotopic xenograft tumors (n=10) were treated with the BET bromodomain inhibitor CPI203 (10 mg/kg) or vehicle control for 30 days. The collagen content of xenograft tumor sections was stained with Picrosirius Red and analyzed with CTFire software. For RNAseq analysis, nu/nu mice (n=8) bearing orthotopic tumors formed by low-passage human PDAC cells were administered CPI203 or vehicle control twice daily for 3 days. Species-specific differences in gene sequence allowed for the identification of genes expressed and changed in both the stroma (mouse) and cancer cells (human).
Results: Analysis of fiber alignment, angle and length revealed that collagen fibers were significantly shorter (161 μm vs. 311 μm, p<0.001) and less organized (0.156 vs. 0.295, p<0.05) in tumors from mice treated with CPI203 relative to controls. Consistent with these changes, RNAseq analysis identified ten collagens and thirty-seven matrix-remodeling enzymes that were down regulated more than two-fold in cancer or stromal cells from CPI203 treated tumors. Gene set enrichment analysis revealed 3 of the top 10 gene sets altered by CPI203 were related to the matrisome (a collection of collagens, extracellular matrix glycoproteins, proteoglycans, ECM-affiliated proteins, ECM regulators, and secreted factors). BET bromodomain inhibition differentially altered the expression of matrisome genes, with 72% of the affected genes expressed in the stroma (p<0.05). Interestingly, BET bromodomain inhibition had large impact on the expression of ECM-affiliated and secreted factors in the stroma (48% and 52%), whereas the expression of collagens was most affected in cancer cells (60%). These results suggest that BET proteins regulate unique matrisome subgroups in both compartments.
Discussion: Leveraging species-specific differences of xenograft tumors, we identified the contribution of stromal and cancer cells to the matrisome of PDAC and defined a major role for the BET family of chromatin adaptors in regulating the expression of its components. Inhibition of these epigenetic regulators leads to shorter and less organized collagen fibers, which has correlated with a less aggressive phenotype in other cancers.

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