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

被引：11

作者：

Ferguson, L. Paige ^{[1
,2
]}

Gatchalian, Jovylyn ^{[3
]}

McDermott, Matthew L. ^{[1
,2
]}

Nakamura, Mari ^{[1
,2
]}

Chambers, Kendall ^{[1
,2
]}

Rajbhandari, Nirakar ^{[1
,2
]}

Lytle, Nikki K. ^{[3
]}

Rosenthal, Sara Brin ^{[4
]}

Hamilton, Michael ^{[1
,2
]}

Albini, Sonia ^{[5
,6
]}

Wartenberg, Martin ^{[7
]}

Zlobec, Inti ^{[7
]}

Galvan, Jose A. ^{[7
]}

Karamitopoulou, Eva ^{[7
]}

Vavinskaya, Vera ^{[8
]}

Wascher, Alexis ^{[9
,10
]}

Lowy, Andrew M. ^{[9
,10
]}

Schuerch, Christian M. ^{[11
,12
]}

Puri, Pier Lorenzo ^{[13
]}

Bruneau, Benoit G. ^{[14
,15
,16
]}

Hargreaves, Diana C. ^{[3
]}

Reya, Tannishtha ^{[1
,2
,17
,18
]}

机构：

[1] Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA

[2] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA

[3] Salk Inst Biol Studies, La Jolla, CA 92037 USA

[4] Univ Calif San Diego, Sch Med, Ctr Computat Biol & Bioinformat, La Jolla, CA 92093 USA

[5] Genethon, F-91000 Evry, France

[6] Univ Evry, Univ Paris Saclay, INSERM, Genethon,Integrare Res Unit,UMR S951, F-91000 Evry, France

[7] Univ Bern, Inst Pathol, Murtenstr 31, CH-3008 Bern, Switzerland

[8] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA

[9] Univ Calif San Diego, Sch Med, Moores Canc Ctr, La Jolla, CA 92093 USA

[10] Univ Calif San Diego, Sch Med, Dept Surg, Div Surg Oncol, La Jolla, CA 92093 USA

[11] Univ Hosp, Dept Pathol & Neuropathol, Tubingen, Germany

[12] Comprehens Canc Ctr Tubingen, Tubingen, Germany

[13] Sanford Burnham Prebys Med Discovery Inst, Dev Aging & Regenerat Program, La Jolla, CA USA

[14] Gladstone Inst, Roddenberry Ctr Stem Cell Biol & Med, San Francisco, CA USA

[15] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA USA

[16] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA

[17] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA

[18] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, Dept Physiol & Cellular Biophys, New York, NY 10032 USA

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

关键词：

CHROMATIN REMODELING COMPLEXES; STEM-CELLS; TRANSCRIPTION FACTORS; SUPER-ENHANCERS; CANCER; COOPERATE; PROMOTES; IDENTITY; THERAPY; MODELS;

D O I：

10.1038/s41467-023-35796-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. Clinical management of pancreatic cancer remains challenging. Here, the authors suggest SMARCD3 as a potential epigenetic dependency establishing the metabolic landscape in aggressive pancreatic cancer cells and as a potential therapeutic target in pancreatic cancer.

引用

页数：17

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