Ferguson, L Paige; Gatchalian, Jovylyn; McDermott, Matthew L; Nakamura, Mari; Chambers, Kendall; Rajbhandari, Nirakar; Lytle, Nikki K; Rosenthal, Sara Brin; Hamilton, Michael; Albini, Sonia; Wartenberg, Martin; Zlobec, Inti; Galván Hernández, José Alberto; Karamitopoulou, Eva; Vavinskaya, Vera; Wascher, Alexis; Lowy, Andrew M; Schürch, Christian M; Puri, Pier Lorenzo; Bruneau, Benoit G; ... (2023). Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma. Nature Communications, 14(1), p. 292. Springer Nature 10.1038/s41467-023-35796-7
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology 04 Faculty of Medicine > Service Sector > Institute of Pathology |
UniBE Contributor: |
Wartenberg, Martin, Zlobec, Inti, Galván Hernández, José Alberto, Karamitopoulou Diamantis, Evanthia |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
2041-1723 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
23 Jan 2023 15:49 |
Last Modified: |
05 Feb 2023 02:25 |
Publisher DOI: |
10.1038/s41467-023-35796-7 |
PubMed ID: |
36653361 |
BORIS DOI: |
10.48350/177689 |
URI: |
https://boris.unibe.ch/id/eprint/177689 |
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