Evidence map›Paper›PMID 39589879›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2024

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 and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed.

  1. Review
  2. Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.Proceedings of the National Academy of Sciences of the United States of America · 2026
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  5. Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

21 authors.

Grigor VaruzhanyanDepartment of Microbiology Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095.
Chia-Chun ChenDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Jack FreelandDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Tian HeDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Wendy TranDepartment of Microbiology Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095.
Kai SongDepartment of Bioengineering, University of California, Los Angeles, CA 90095.
Liang WangDepartment of Microbiology Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095.
Donghui ChengDepartment of Microbiology Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095.
Shili XuDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.ORCID 0000-0002-4933-8673
Gabriella A DibernardoEli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
Favour N EsedebeDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Vipul BhatiaDivision of Hematology/Oncology, Department of Medicine University of California Los Angeles Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.
Mingqi HanDepartment of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Evan R AbtDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.ORCID 0000-0002-3160-7134
Jung Wook ParkDepartment of Pathology, Duke University School of Medicine, Durham, NC 27710.
Sanaz MemarzadehDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
David B ShackelfordJonsson Comprehensive Cancer Center, the David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
John K LeeDivision of Hematology/Oncology, Department of Medicine University of California Los Angeles Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.
Thomas G GraeberDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.ORCID 0000-0001-8574-9181
Orian S ShirihaiDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Owen N WitteDepartment of Microbiology Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095.ORCID 0000-0003-4461-4533

Funding

Tumor Immunology and Immunotherapy (TII)P30CA016042 · UNIVERSITY OF CALIFORNIA LOS ANGELES · 1985 to 2025
$29.3M
UCLA SPORE IN PROSTATE CANCERP50CA092131 · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2002 to 2005
$8.7M
TUMOR CELL SURFACES AND CHROMOSOMEST32CA009056 · UNIVERSITY OF CALIFORNIA LOS ANGELES · 1985 to 2025
$2.8M
UCLA SPORE in Brain CancerP50CA211015 · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2025 to 2025
$2.2M
In vivo imaging of mitochondria structure and function in therapy resistant lung tumorsR01CA267721 · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2025 to 2025
$620k
Imaging mitochondrial heterogeneity in LKB1 mutant lung cancerR01CA208642 · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2025 to 2025
$429k
Reactivating p53 Function with a Novel Structure-based Peptide as a Therapeutic Approach for Overcoming Platinum ResistanceI01BX004651 · VA · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · PI Sanaz Memarzadeh · 2023 to 2023
–
BCCMA: Overcoming chemoresistance in ovarian cancer: Targeting Unique Vulnerabilities in Neuroendocrine-like Ovarian Cancer CellsI01BX006019 · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2025 to 2025
–
BLRD VA I01 BX004651BLRD VA I01 BX006019G. Harold and Leila Y. Mathers Foundation (Mathers Foundation) 01NCI NIH HHS DP2 CA271301NCI NIH HHS P30 CA016042NCI NIH HHS P50 CA092131NCI NIH HHS P50 CA211015NCI NIH HHS R01 CA208642NCI NIH HHS R01 CA222877NCI NIH HHS R01 CA267721NCI NIH HHS T32 CA009056NIH HHS S10 OD026917NIH (NIH) 1 S10 OD026917-01A1NIH (NIH) 2 P30 CA016042-44NIH R01 Grant R01CA222877ÂNIH UCLA SPORE in Prostate Cancer P50CA092131ÂParker Institute for Cancer Immunotherapy (PICI) 01UCLA Dissertation Year Fellowship 01UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award 01UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Hal Gaba Director's Fund for Cancer Stem Cell Research 01UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research predoctoral fellowship 01UCLA Tumor Cell Biology Training Program (USHHS) Ruth L. Kirschstein Institutional national Research Service Award NIH T32 CA-009056University of California-Historically Black Colleges and Universities (UC-HBCU) Initiative Fellowship provided by University of California Office of the President (UCOP). 01Veteran Affairs funds I01BX006019
6 · The paper itself

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.

Indexed as

Basic Helix-Loop-Helix ProteinsDisease ProgressionMitochondriaOxidative PhosphorylationPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaAnimalsCell Line, TumorCell ProliferationGene Expression Regulation, NeoplasticHumansMaleMiceNeuroendocrine TumorsProstatic NeoplasmsASCL1 protein, humanBasic Helix-Loop-Helix ProteinsPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPPARGC1A protein, humanASCL1lung canceroxidative phosphorylationPGC-1aprostate cancer

Identifiers

PMID39589879
PMCPMC11626175

What Socratic holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.