- Liang, Gaoyang;
- Oh, Tae Gyu;
- Hah, Nasun;
- Tiriac, Hervé;
- Shi, Yu;
- Truitt, Morgan L;
- Antal, Corina E;
- Atkins, Annette R;
- Li, Yuwenbin;
- Fraser, Cory;
- Ng, Serina;
- Pinto, Antonio FM;
- Nelson, Dylan C;
- Estepa, Gabriela;
- Bashi, Senada;
- Banayo, Ester;
- Dai, Yang;
- Liddle, Christopher;
- Yu, Ruth T;
- Hunter, Tony;
- Engle, Dannielle D;
- Han, Haiyong;
- Von Hoff, Daniel D;
- Downes, Michael;
- Evans, Ronald M
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of 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. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.