PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity
Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.
Authors
- Vipul Bhatia (ORCID: https://orcid.org/0000-0002-4091-8866)
- He Tian (ORCID: https://orcid.org/0000-0002-5388-0297)
- Thomas G. Graeber (ORCID: https://orcid.org/0000-0001-8574-9181)
- Chia‐Chun Chen (ORCID: https://orcid.org/0000-0001-6491-0482)
- Liang Wang (ORCID: https://orcid.org/0000-0002-4052-1316)
- Favour N. Esedebe (ORCID: https://orcid.org/0000-0001-6167-0647)
- Grigor Varuzhanyan
- Sanaz Memarzadeh
- Shili Xu (ORCID: https://orcid.org/0000-0002-4933-8673)
- Jack Freeland (ORCID: https://orcid.org/0000-0002-8547-1869)
- John K. Lee (ORCID: https://orcid.org/0000-0002-6570-2180)
- Orian Shirihai
- Kai Song (ORCID: https://orcid.org/0000-0002-3654-2616)
- Evan R. Abt
- David B. Shackelford (ORCID: https://orcid.org/0000-0002-8270-898X)
- Wendy Tran (ORCID: https://orcid.org/0000-0002-7851-4859)
- Owen N. Witte (ORCID: https://orcid.org/0000-0003-4461-4533)
- Gabriella DiBernardo (ORCID: https://orcid.org/0000-0001-8022-7288)
- Donghui Cheng
- Mingqi Han (ORCID: https://orcid.org/0000-0003-2070-5967)
- Jung Wook Park (ORCID: https://orcid.org/0000-0003-4798-9621)
Institutions
- Ben-Gurion University of the Negev (IL)
- California NanoSystems Institute (US)
- University of California, Los Angeles (US)
- Duke University (US)
- Fred Hutch Cancer Center (US)
- Parker Institute for Cancer Immunotherapy (US)
- Broad Center (US)
- VA Greater Los Angeles Healthcare System (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1073/pnas.2416882121
- Citations
- 11
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- U.S. Department of Veterans Affairs
- W. M. Keck Foundation
- G. Harold and Leila Y. Mathers Foundation
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health
- School of Medicine, Duke University
- University of California, Los Angeles
- Office of the President, University of California
- Jonsson Comprehensive Cancer Center
- David Geffen School of Medicine, University of California, Los Angeles
- California NanoSystems Institute