PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity

• 成果类型: Article
• 署名作者: Varuzhanyan, Grigor; Chen, Chia-Chun; Freeland, Jack; He, Tian; Tran, Wendy; Song, Kai; Wang, Liang; Cheng, Donghui; Xu, Shili; Dibernardo, Gabriella A.; Esedebe, Favour N.; Bhatia, Vipul; Han, Mingqi; Abt, Evan R.; Park, Jung Wook; Memarzadeh, Sanaz; Shackelford, David B.; Lee, John K.; Graeber, Thomas G.; Shirihai, Orian S.; Witte, Owen N.
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; UCLA Jonsson Comprehensive Cancer Center; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; UCLA Jonsson Comprehensive Cancer Center; University of California System; University of California Los Angeles; Fred Hutchinson Cancer Center; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Duke University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Greater Los Angeles Healthcare System; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Ben-Gurion University of the Negev; University of California System; University of California Los Angeles
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13417
• DOI: 10.1073/pnas.2416882121
• 发表日期: 2024-12-03
• 关键词: oxidative-phosphorylation; lineage plasticity; pgc-1 coactivators; metabolism; biogenesis; resistance; target

摘要

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-1 alpha), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC- 1 alpha 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-1 alpha expression and OXPHOS activity. PGC-1 alpha inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1 alpha 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-1 alpha as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.