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

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

doi:10.1073/pnas.2416882121

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

Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2416882121. doi: 10.1073/pnas.2416882121. Epub 2024 Nov 26.

Authors

Grigor Varuzhanyan¹, Chia-Chun Chen², Jack Freeland^{2

3}, Tian He², Wendy Tran¹, Kai Song⁴, Liang Wang¹, Donghui Cheng^{1

5}, Shili Xu^{2

6

7}, Gabriella A Dibernardo^{5

8}, Favour N Esedebe^{2

9}, Vipul Bhatia^{10

11}, Mingqi Han¹², Evan R Abt², Jung Wook Park¹³, Sanaz Memarzadeh^{2

5

7

8

14

15}, David B Shackelford^{7

12}, John K Lee^{10

11}, Thomas G Graeber^{2

5

6

7

9

16

17}, Orian S Shirihai^{2

3

18

19}, Owen N Witte^{1

2

5

7

15

20}

Affiliations

¹ Department of Microbiology Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095.
² Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
³ Molecular Biology Interdepartmental Program, University of California, Los Angeles, CA 90095.
⁴ Department of Bioengineering, University of California, Los Angeles, CA 90095.
⁵ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
⁶ Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
⁷ Jonsson Comprehensive Cancer Center, the David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
⁸ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
⁹ Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA 90095.
¹⁰ Division of Hematology/Oncology, Department of Medicine University of California Los Angeles Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.
¹¹ Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109.
¹² Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
¹³ Department of Pathology, Duke University School of Medicine, Durham, NC 27710.
¹⁴ The Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073.
¹⁵ Molecular Biology Institute, University of California, Los Angeles, CA 90095.
¹⁶ California NanoSystems Institute, University of California, Los Angeles, CA 90095.
¹⁷ UCLA Metabolomics Center, University of California, Los Angeles, CA 90095.
¹⁸ University of California Los Angeles Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
¹⁹ Department of Clinical Biochemistry, School of Medicine, Ben Gurion University of The Negev, Beer-Sheva 8410501, Israel.
²⁰ Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, CA 90095.

Abstract

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.

Keywords: ASCL1; PGC-1a; lung cancer; oxidative phosphorylation; prostate cancer.

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors* / genetics
Basic Helix-Loop-Helix Transcription Factors* / metabolism
Cell Line, Tumor
Cell Proliferation
Disease Progression*
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Mitochondria* / metabolism
Neuroendocrine Tumors / genetics
Neuroendocrine Tumors / metabolism
Neuroendocrine Tumors / pathology
Oxidative Phosphorylation*
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / metabolism
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology

Substances

Basic Helix-Loop-Helix Transcription Factors
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PPARGC1A protein, human
ASCL1 protein, human

Abstract

MeSH terms

Substances

Grants and funding