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

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 Wartenberg, Inti Zlobec, José A. Galván, Eva Karamitopoulou, Vera Vavinskaya, Alexis Wascher, Andrew M. Lowy, Christian M. Schürch, Pier Lorenzo Puri, Benoit G. Bruneau, Diana C. Hargreaves () and Tannishtha Reya ()
Additional contact information
L. Paige Ferguson: University of California San Diego School of Medicine
Jovylyn Gatchalian: Salk Institute for Biological Studies
Matthew L. McDermott: University of California San Diego School of Medicine
Mari Nakamura: University of California San Diego School of Medicine
Kendall Chambers: University of California San Diego School of Medicine
Nirakar Rajbhandari: University of California San Diego School of 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
Sonia Albini: Genethon
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
Andrew M. Lowy: 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
Diana C. Hargreaves: Salk Institute for Biological Studies
Tannishtha Reya: University of California San Diego School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-35796-7

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