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Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma

Author

Listed:
  • L. Paige Ferguson

    (University of California San Diego School of Medicine
    Sanford Consortium for Regenerative Medicine)

  • Jovylyn Gatchalian

    (Salk Institute for Biological Studies)

  • Matthew L. McDermott

    (University of California San Diego School of Medicine
    Sanford Consortium for Regenerative Medicine)

  • Mari Nakamura

    (University of California San Diego School of Medicine
    Sanford Consortium for Regenerative Medicine)

  • Kendall Chambers

    (University of California San Diego School of Medicine
    Sanford Consortium for Regenerative Medicine)

  • Nirakar Rajbhandari

    (University of California San Diego School of Medicine
    Sanford Consortium for Regenerative Medicine)

  • Nikki K. Lytle

    (Salk Institute for Biological Studies)

  • Sara Brin Rosenthal

    (University of California San Diego School of Medicine)

  • Michael Hamilton

    (University of California San Diego School of Medicine
    Sanford Consortium for Regenerative Medicine)

  • Sonia Albini

    (Genethon
    Genethon, Integrare research unit UMR_S951)

  • Martin Wartenberg

    (University of Bern)

  • Inti Zlobec

    (University of Bern)

  • José A. Galván

    (University of Bern)

  • Eva Karamitopoulou

    (University of Bern)

  • Vera Vavinskaya

    (University of California San Diego School of Medicine)

  • Alexis Wascher

    (University of California San Diego School of Medicine
    Division of Surgical Oncology, University of California San Diego School of Medicine)

  • Andrew M. Lowy

    (University of California San Diego School of Medicine
    Division of Surgical Oncology, University of California San Diego School of Medicine)

  • Christian M. Schürch

    (University Hospital and Comprehensive Cancer Center Tübingen)

  • Pier Lorenzo Puri

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Benoit G. Bruneau

    (Roddenberry Center for Stem Cell Biology and Medicine
    University of California San Francisco
    University of California San Francisco)

  • Diana C. Hargreaves

    (Salk Institute for Biological Studies)

  • Tannishtha Reya

    (University of California San Diego School of Medicine
    Sanford Consortium for Regenerative Medicine
    University of California San Diego School of Medicine
    Columbia University Medical Center)

Abstract

Pancreatic cancer is characterized by extensive resistance to conventional therapies, making clinical management a challenge. Here we map the epigenetic dependencies of cancer stem cells, cells that preferentially evade therapy and drive progression, and identify SWI/SNF complex member SMARCD3 as a regulator of pancreatic cancer cells. Although SWI/SNF subunits often act as tumor suppressors, we show that SMARCD3 is amplified in cancer, enriched in pancreatic cancer stem cells and upregulated in the human disease. Diverse genetic mouse models of pancreatic cancer and stage-specific Smarcd3 deletion reveal that Smarcd3 loss preferentially impacts established tumors, improving survival especially in context of chemotherapy. Mechanistically, SMARCD3 acts with FOXA1 to control lipid and fatty acid metabolism, programs associated with therapy resistance and poor prognosis in cancer. These data identify SMARCD3 as an epigenetic modulator responsible for establishing the metabolic landscape in aggressive pancreatic cancer cells and a potential target for new therapies.

Suggested Citation

  • L. Paige Ferguson & Jovylyn Gatchalian & Matthew L. McDermott & Mari Nakamura & Kendall Chambers & Nirakar Rajbhandari & Nikki K. Lytle & Sara Brin Rosenthal & Michael Hamilton & Sonia Albini & Martin, 2023. "Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35796-7
    DOI: 10.1038/s41467-023-35796-7
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    References listed on IDEAS

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