2. Academic Validation
  3. IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2

IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2

  • Nat Commun. 2026 Jun 6. doi: 10.1038/s41467-026-74058-0.
Po Zhang # 1 2,  Weichi Wu # 1 2 3,  Tengfei Huang 1 2 3,  Xujia Wu 1 2,  Donghai Wang 1 2 3,  Huairui Yuan 1 2,  Suchet Taori 1 2,  Fanen Yuan 1 2,  Frank P Vendetti 4,  Rui Wang 1 2 3,  Tingting Duan 1 2,  Hailong Mi 1 2,  Huan Li 1 2 3,  Kailin Yang 5,  Daqi Li 1 2 3,  Ahmed Habib 1 6,  Briana C Prager 7,  Ryan C Gimple 8,  Pascal O Zinn 1 6,  Kalil Abdullah 1 6,  Christopher Bakkenist 1 4,  Junran Zhang 9,  Qiulian Wu 1 2 3,  Jeremy N Rich 10 11 12 13
Affiliations

Affiliations

  • 1 UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 2 Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
  • 4 Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 5 Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa, IA, USA.
  • 6 Department of Neurosurgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • 7 Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
  • 8 Department of Medical Oncology, Washington University in Saint Louis, Saint Louis, MO, USA.
  • 9 Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, OH, USA.
  • 10 UPMC Hillman Cancer Center, Pittsburgh, PA, USA. [email protected].
  • 11 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. [email protected].
  • 12 Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 13 Depssartment of Neurology, University of North Carolina, Chapel Hill, NC, USA. [email protected].
  • # Contributed equally.
PMID: 42251046 DOI: 10.1038/s41467-026-74058-0
Abstract

Drivers of therapeutic resistance in Cancer include evolving tumor cell heterogeneity and the tumor microenvironment (TME). We find that increased matrix stiffness promotes radioresistance in glioblastoma (GBM) and maintains tumor cell hierarchies. Differential gene expression reveals that stiff matrices induce expression of IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) through YAP1 and TEAD transcription factors in GBM stem cells (GSCs). IQGAP3 promotes GSC self-renewal and survival upon radiation treatment through binding and stabilization of core stem cell transcription factor, SOX2. Targeting IQGAP3 reduces SOX2 protein levels in vitro and in vivo, increasing GSC radiosensitivity and inhibiting tumor growth. Structure-function drug screening of FDA-approved agents blocking IQGAP3-SOX2 binding identifies trimetrexate as a brain penetrant pharmacologic disruptor of IQGAP3 function in radioresistance, sensitizing GSCs to radiotherapy. These results identify molecular underpinnings for biomechanical promotion of Cancer stem cell maintenance and therapeutic resistance, informing therapeutic strategies to augment efficacy of radiotherapy.

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