Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration
Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear. Here, we show that induction of somatic mutations in subventricular zone (SVZ) progenitor cells leads to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other's loci and to downstream target genes then determines the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in specifying highly migratory neural stem cell (NSC)/astrocyte-like tumor cell types, which are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.
Authors
- Kathryn J. Brayer (ORCID: https://orcid.org/0000-0002-1098-941X)
- Hideaki Suzuki (ORCID: https://orcid.org/0000-0002-0410-6940)
- Rahul K. Kollipara
- Jane E. Johnson (ORCID: https://orcid.org/0000-0003-3829-8116)
- Conner M. Mertz (ORCID: https://orcid.org/0000-0001-8710-212X)
- Robert Bachoo (ORCID: https://orcid.org/0000-0001-9229-9342)
- Mark D. Borromeo
- Tou Yia Vue (ORCID: https://orcid.org/0000-0002-5903-9968)
- Estrella Villicana (ORCID: https://orcid.org/0009-0008-6079-2827)
- Luis E. Paez-Beltran (ORCID: https://orcid.org/0009-0000-2223-5714)
- Q. Richard Lu (ORCID: https://orcid.org/0000-0001-6846-9014)
- Rebekka H. Anderson
- Matthew S. Keith
- Bianca L. Myers (ORCID: https://orcid.org/0000-0001-8149-0643)
- Yunee Lo
- Jessie Newville (ORCID: https://orcid.org/0000-0002-8590-7968)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- University of New Mexico (US)
- Southwestern Medical Center (US)
- New Mexico Cancer Center (US)
- UNM Comprehensive Cancer Center
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1038/s41467-024-54750-9
- Citations
- 30
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 8.55
Funders
- Cancer Prevention and Research Institute of Texas
- National Institute on Alcohol Abuse and Alcoholism
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke