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; Tannishtha Reya

doi:10.1038/s41467-023-35796-7

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

Nat Commun. 2023 Jan 18;14(1):292. doi: 10.1038/s41467-023-35796-7.

Authors

L Paige Ferguson^{1

2}, Jovylyn Gatchalian³, Matthew L McDermott^{1

2}, Mari Nakamura^{1

2}, Kendall Chambers^{1

2}, Nirakar Rajbhandari^{1

2}, Nikki K Lytle³, Sara Brin Rosenthal⁴, Michael Hamilton^{1

2}, Sonia Albini^{5

6}, Martin Wartenberg⁷, Inti Zlobec⁷, José A Galván⁷, Eva Karamitopoulou⁷, Vera Vavinskaya⁸, Alexis Wascher^{9

10}, Andrew M Lowy^{9

10}, Christian M Schürch¹¹, Pier Lorenzo Puri¹², Benoit G Bruneau^{13

14

15}, Diana C Hargreaves¹⁶, Tannishtha Reya^{17

18

19

20}

Affiliations

¹ Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA.
² Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
³ Salk Institute for Biological Studies, La Jolla, CA, USA.
⁴ Center for Computational Biology and Bioinformatics, University of California San Diego School of Medicine, La Jolla, CA, USA.
⁵ Genethon, 91000, EVRY, France.
⁶ Université Paris-Saclay, Univ Evry, Inserm, Genethon, Integrare research unit UMR_S951, 91000, Evry, France.
⁷ Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland.
⁸ Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA.
⁹ Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA.
¹⁰ Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA, USA.
¹¹ Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany.
¹² Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹³ Gladstone Institutes, Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA, USA.
¹⁴ Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
¹⁶ Salk Institute for Biological Studies, La Jolla, CA, USA. dhargreaves@salk.edu.
¹⁷ Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA. tr2726@cumc.columbia.edu.
¹⁸ Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA. tr2726@cumc.columbia.edu.
¹⁹ Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA. tr2726@cumc.columbia.edu.
²⁰ Department of Physiology and Cellular Biophysics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA. tr2726@cumc.columbia.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / pathology
Epigenesis, Genetic
Humans
Mice
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding