Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration

Bianca L. Myers, Kathryn J. Brayer, Luis E. Paez-Beltran, Estrella Villicana, Matthew S. Keith, Hideaki Suzuki, Jessie Newville, Rebekka H. Anderson, Yunee Lo, Conner M. Mertz, Rahul K. Kollipara, Mark D. Borromeo, Q. Richard Lu, Robert M. Bachoo, Jane E. Johnson and Tou Yia Vue ()
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Bianca L. Myers: University of New Mexico Health Sciences Center
Kathryn J. Brayer: University of New Mexico Comprehensive Cancer Center
Luis E. Paez-Beltran: University of New Mexico Health Sciences Center
Estrella Villicana: University of New Mexico Health Sciences Center
Matthew S. Keith: University of New Mexico Health Sciences Center
Hideaki Suzuki: University of New Mexico Health Sciences Center
Jessie Newville: University of New Mexico Health Sciences Center
Rebekka H. Anderson: University of New Mexico Health Sciences Center
Yunee Lo: University of New Mexico Health Sciences Center
Conner M. Mertz: University of New Mexico Health Sciences Center
Rahul K. Kollipara: University of Texas Southwestern Medical Center
Mark D. Borromeo: University of Texas Southwestern Medical Center
Q. Richard Lu: Brain Tumor Center, EHCB, Cincinnati Children’s Hospital Medical Center
Robert M. Bachoo: University of Texas Southwestern Medical Center
Jane E. Johnson: University of Texas Southwestern Medical Center
Tou Yia Vue: University of New Mexico Health Sciences Center

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54750-9

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