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Inhibiting stromal Class I HDACs curbs pancreatic cancer progression

Author

Listed:
  • Gaoyang Liang

    (Salk Institute for Biological Studies)

  • Tae Gyu Oh

    (Salk Institute for Biological Studies
    University of Oklahoma Health Sciences Center)

  • Nasun Hah

    (Salk Institute for Biological Studies)

  • Hervé Tiriac

    (University of California San Diego)

  • Yu Shi

    (Salk Institute for Biological Studies
    Bristol Myer Squibb)

  • Morgan L. Truitt

    (Salk Institute for Biological Studies)

  • Corina E. Antal

    (Salk Institute for Biological Studies
    University of California San Diego)

  • Annette R. Atkins

    (Salk Institute for Biological Studies)

  • Yuwenbin Li

    (Salk Institute for Biological Studies)

  • Cory Fraser

    (HonorHealth Scottsdale Osborn Medical Center and Shea Medical Center)

  • Serina Ng

    (The Translational Genomic Research Institute)

  • Antonio F. M. Pinto

    (Salk Institute for Biological Studies)

  • Dylan C. Nelson

    (Salk Institute for Biological Studies)

  • Gabriela Estepa

    (Salk Institute for Biological Studies)

  • Senada Bashi

    (Salk Institute for Biological Studies)

  • Ester Banayo

    (Salk Institute for Biological Studies)

  • Yang Dai

    (Salk Institute for Biological Studies)

  • Christopher Liddle

    (University of Sydney, Westmead Hospital)

  • Ruth T. Yu

    (Salk Institute for Biological Studies)

  • Tony Hunter

    (Salk Institute for Biological Studies)

  • Dannielle D. Engle

    (Salk Institute for Biological Studies)

  • Haiyong Han

    (The Translational Genomic Research Institute)

  • Daniel D. Von Hoff

    (HonorHealth Scottsdale Osborn Medical Center and Shea Medical Center
    The Translational Genomic Research Institute)

  • Michael Downes

    (Salk Institute for Biological Studies)

  • Ronald M. Evans

    (Salk Institute for Biological Studies)

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.

Suggested Citation

  • 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 , 2023. "Inhibiting stromal Class I HDACs curbs pancreatic cancer progression," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42178-6
    DOI: 10.1038/s41467-023-42178-6
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    References listed on IDEAS

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