Epigenetic regulation of the tumor microenvironment in pancreatic cancer
Final Report Abstract
In this research project, we characterized the non-cellular content of the PDAC stroma for the first time. For this we utilized three different patient derived xenografts that were orthotopically implanted into pancreata of immunodeficient mice. This model allowed for separation of the mouse derived stroma from the human derived cancer. Importantly, we found that matrisome gene signatures found in these PDX models were very similar to signatures found in patient tumors, that we had laser-micro dissected. Suprisingly, stromal cells were not the only major producing matrix cells, but also cancer cells contributed substantially (40%) to the make-up of the PDAC matrisome. In fact, most of the genes were expressed by both compartments (stroma and cancer), and not as previously described majorly by the stromal cells. Furthermore, we deciphered the epigenetic role of BET bromodomain proteins for the expression of the PDAC matrisome. BET proteins were able to abrogate a stroma-cancer cross-talk induced effect on matrisome expression in a co-culture model. We also found that this effect is likely driven by contactdependent communication. Finally, the alteration of tumor-stroma crosstalk led to significant growth reduction in an orthotopic tumor model, in which the tumor cells themselves were insensitive to BETi in culture, suggesting the importance of modulating the cancer-stroma crosstalk in PDAC tumors. We were also able to calculate a matrisome signature classifier to predict long-versus short term survival in an independent PDAC cohort with 532 worldwide resected PDAC patients, again strengthening the importance of the PDAC matrisome to the biology of tumors. In summary, we have newly characterized a new compartment of PDAC tumors, and defined one pharmacological target to alter a large percentage of extracellular matrix genes in order to slow tumor growth. These data will potentially lead to a new understanding of these deadly tumors and offers multiple new targets for anticancer treatment. This project has led to multiple talks and awards for the DFG scholar. It also offers a great basis to continue research as a surgeon-scientist.
Publications
- Reprogramming The PDAC Stroma By Targeting The Bet Family Of Chromatin Adaptors Pancreas, APA 2017, American Pancreatic Association, San Diego, November 2017
K.C. Honselmann, A. Nakagawa, D. Ting, M.Ligorio, E. Tai, M. Mino-Kenudson, K.D. Lillemoe, C. Fernández-del Castillo, A.L. Warshaw, A.S. Liss
- Targeting epigenetic regulation of the Matrisome to remodel tumor collagen in pancreatic cancer, DDW 2017 – Digestive Disease Week, Chicago, June 2017. Gastroenterology 2017
Honselmann KC, Mino-Kenudson M, Nakagawa A, Lilloemoe KD, Fernandez del Castillo CF, Warshaw AL, Liss AS
(See online at https://doi.org/10.1016/S0016-5085(17)34030-1) - Targeting epigenetics to reprogram the pancreatic cancer stroma. DGCH 2018, Deutscher Chirurgenkongress, Berlin, März 2018
Kim Honselmann, D. Ting, M. Kenudson, C. Fernandez-del Castillo, A. Warshaw, A. Liss
