Inhibiting stromal Class I HDACs curbs pancreatic cancer progression

Gaoyang Liang; Tae Gyu Oh; Nasun Hah; Hervé Tiriac; Yu Shi; Morgan L Truitt; Corina E Antal; Annette R Atkins; Yuwenbin Li; Cory Fraser; Serina Ng; Antonio F M Pinto; Dylan C Nelson; Gabriela Estepa; Senada Bashi; Ester Banayo; Yang Dai; Christopher Liddle; Ruth T Yu; Tony Hunter; Dannielle D Engle; Haiyong Han; Daniel D Von Hoff; Michael Downes; Ronald M Evans

doi:10.1038/s41467-023-42178-6

Inhibiting stromal Class I HDACs curbs pancreatic cancer progression

Nat Commun. 2023 Dec 6;14(1):7791. doi: 10.1038/s41467-023-42178-6.

Authors

Gaoyang Liang¹, Tae Gyu Oh^{1

2}, Nasun Hah³, Hervé Tiriac⁴, Yu Shi^{5

6}, Morgan L Truitt¹, Corina E Antal^{1

7}, Annette R Atkins¹, Yuwenbin Li¹, Cory Fraser⁸, Serina Ng⁹, Antonio F M Pinto¹⁰, Dylan C Nelson¹, Gabriela Estepa¹, Senada Bashi¹, Ester Banayo¹, Yang Dai¹, Christopher Liddle¹¹, Ruth T Yu¹, Tony Hunter⁵, Dannielle D Engle¹², Haiyong Han⁹, Daniel D Von Hoff^{8

9}, Michael Downes¹³, Ronald M Evans¹⁴

Affiliations

¹ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
² Department of Oncology Science, OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA.
³ Next Generation Sequencing Core, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
⁴ Department of Surgery, University of California San Diego, La Jolla, CA, 92093, USA.
⁵ Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
⁶ Bristol Myer Squibb, 10300 Campus Point Drive, Suite 100, San Diego, CA, 92121, USA.
⁷ Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.
⁸ HonorHealth Scottsdale Osborn Medical Center and Shea Medical Center, Scottsdale, AZ, 85260, USA.
⁹ Molecular Medicine Division, The Translational Genomic Research Institute, Phoenix, AZ, 85004, USA.
¹⁰ Mass Spectrometry Core, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
¹¹ Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW, 2145, Australia.
¹² Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
¹³ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA. downes@salk.edu.
¹⁴ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA. evans@salk.edu.

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.

MeSH terms

Animals
Carcinogenesis / pathology
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / metabolism
Cell Line, Tumor
Fibroblasts / metabolism
Mice
Pancreas / metabolism
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism
Tumor Microenvironment

Abstract

MeSH terms

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