RESETTING EPIGENETIC PROGRAM SWITCHES CURBS PANCREATIC CANCER PROGRESSION

Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors inducing the transcriptional programs driving stromal activation and PDAC progression. HDACs facilitate the switch from lipogenic to pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. In pancreatic tumor cells, HDACs switch epithelial to neoplastic transcriptional programs, propelling robust proliferation and DNA repair. Treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models arrests tumor progression and reduces stromal activation. Notably, Ent synergizes with DNA damaging agents to prolong survival, highlighting a potential for HDAC inhibitors in PDAC therapy.