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.
Proceedings of the National Academy of Sciences of the United States of America. 2024 Nov 26 [Epub]
Grigor Varuzhanyan, Chia-Chun Chen, Jack Freeland, Tian He, Wendy Tran, Kai Song, Liang Wang, Donghui Cheng, Shili Xu, Gabriella A Dibernardo, Favour N Esedebe, Vipul Bhatia, Mingqi Han, Evan R Abt, Jung Wook Park, Sanaz Memarzadeh, David B Shackelford, John K Lee, Thomas G Graeber, Orian S Shirihai, Owen N Witte
Department of Microbiology Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095., Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095., Department of Bioengineering, University of California, Los Angeles, CA 90095., Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095., Division of Hematology/Oncology, Department of Medicine University of California Los Angeles Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095., Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Department of Pathology, Duke University School of Medicine, Durham, NC 27710., Jonsson Comprehensive Cancer Center, the David Geffen School of Medicine, University of California, Los Angeles, CA 90095.