BioProject

Pancreatic ductal adenocarcinoma (PDAC) is extraordinarily chemoresistant and the abundant stromal content of these tumors contributes to the ineffective treatment of this disease. More...

Pancreatic ductal adenocarcinoma (PDAC) is extraordinarily chemoresistant and the abundant stromal content of these tumors contributes to the ineffective treatment of this disease. While the genetic alterations of PDAC have been well characterized, the epigenetic pathways regulating PDAC remain, for the most part, elusive. Employing an in vivo shRNA screen targeting epigenetic regulators, we identified members of the BET family of chromatin adaptors as key regulators of PDAC cell growth and maintenance of the tumor stroma. BET family members contribute to PDAC cell growth by modulating the activity of two key transcriptional programs, MYC and GLI. Within the cancer cells, BET inhibition also results in down-regulation of a key mediator of the tumor microenvironment, SHH, corresponding to a decrease in the stromal content of tumors. Taken together, these results suggest that therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Overall design: Total RNA was isolated from 4 untreated PDAC cell lines or those exposedto the BET bromodomain inhibibitor CPI203 (1.6 uM) or control DMSO for 5 and 10 hours Less...