INSM1 governs a neuronal progenitor state that drives glioblastoma in a human stem cell model
Glioblastoma is a lethal brain cancer marked by functional plasticity driven by tumor cell-intrinsic mutations and their interplay with developmental programs. To investigate how canonical glioblastoma mutations promote functional plasticity, we have developed an isogenic human neural stem cell (NSC) model of glioblastoma by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increases TERT expression during serial mutagenesis, but only triple mutant NSCs reliably form lethal brain tumors in vivo that recapitulate glioblastoma. Tumor cell evolution triggers stress-related metabolic changes and transitions toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed in human glioblastoma tumors and, during cortical development, in intermediate progenitor cells, which give rise to neurons. Remarkably, INSM1 knockdown in triple mutant NSCs and primary glioblastoma cells disrupts oncogenic gene expression and function and inhibits the in vivo tumorigenicity of triple mutant NSCs, highlighting the functional importance of an intermediate progenitor cell-like cell state in glioblastoma pathogenesis.
Authors
- Ryan T. Cleary (ORCID: https://orcid.org/0000-0002-2018-3559)
- Xuan Qu (ORCID: https://orcid.org/0000-0003-1436-3315)
- Matthew Ishahak (ORCID: https://orcid.org/0000-0002-7494-6048)
- Punn Augsornworawat (ORCID: https://orcid.org/0000-0001-8602-5433)
- Albert H. Kim (ORCID: https://orcid.org/0000-0002-1751-8493)
- Timothy Woodiwiss
- Diane D. Mao
- Alexandre Teixeira Vessoni (ORCID: https://orcid.org/0000-0001-9170-5185)
- Luís F.Z. Batista (ORCID: https://orcid.org/0000-0002-7538-3240)
- Rowland H. Han (ORCID: https://orcid.org/0000-0002-8615-8532)
- Maryam Borhani‐Haghighi (ORCID: https://orcid.org/0000-0003-0308-2948)
- Devi Annamalai (ORCID: https://orcid.org/0000-0001-7225-7663)
- Colin McCornack (ORCID: https://orcid.org/0000-0002-7781-1456)
- Rajanikanth Vangipurapu (ORCID: https://orcid.org/0000-0003-0676-3140)
- Sangami Pugazenthi (ORCID: https://orcid.org/0000-0002-5179-5232)
- Patrick DeSouza (ORCID: https://orcid.org/0000-0003-3600-4452)
- Jeffrey R. Millman (ORCID: https://orcid.org/0000-0003-0426-3492)
- Hao Chen (ORCID: https://orcid.org/0000-0002-8874-0673)
- Ting Wang (ORCID: https://orcid.org/0000-0002-6800-242X)
- Jessica Kline (ORCID: https://orcid.org/0000-0002-8090-1209)
- Hiroko Yano (ORCID: https://orcid.org/0000-0001-6548-0920)
- Yiwei Fu
- Darby Agovino (ORCID: https://orcid.org/0000-0002-6543-4235)
- Braxton Sizemore (ORCID: https://orcid.org/0009-0002-9200-2101)
Institutions
- University of Iowa (US)
- Siriraj Hospital (TH)
- Washington University in St. Louis (US)
- Mahidol University (TH)
- Brain Tumour Charity (GB)
- Sanofi (France) (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-07
- DOI
- https://doi.org/10.1038/s41467-025-66371-x
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00