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Inhibiting stromal Class I HDACs curbs pancreatic cancer progression
Gaoyang Liang1, Tae Gyu Oh1,2, Nasun Hah3
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
Abstract:
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.
Insights
Histone deacetylases (HDACs) drive pancreatic cancer
Area of Science:
- Epigenetics
- Cancer Biology
- Tumor Microenvironment
Background:
- Pancreatic ductal adenocarcinoma (PDAC) features a desmoplastic tumor microenvironment (TME) that promotes therapeutic resistance.
- Oncogenic lesions manipulate stromal epigenetic machinery to create this resistant TME.
Purpose of the Study:
- To investigate the role of Class I histone deacetylases (HDACs) in regulating pancreatic stromal fibroblasts.
- To explore the therapeutic potential of HDAC inhibition (HDACi) in PDAC.
Main Methods:
- Utilized mouse models of PDAC.
- Depleted HDACs in cancer-associated fibroblasts (CAFs).
- Treated PDAC models with the HDAC inhibitor entinostat (Ent).
Main Results:
- Class I HDACs induce pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic fibroblasts via SRF and FOXM1.
- HDACs promote pro-tumorigenic crosstalk through LIF expression.
- HDAC depletion/inhibition in CAFs reduced stromal activation and tumor progression in PDAC models.
- HDACi enriched a lipogenic fibroblast subpopulation in the PDAC stroma.
Conclusions:
- Class I HDACs are key epigenetic regulators of the PDAC stroma.
- Targeting HDACs epigenetically modulates the PDAC stroma, offering a potential therapeutic strategy.
- HDAC inhibition demonstrates promise in curbing PDAC progression by targeting stromal components.
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