Journal article
IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2
Nature communications, Vol.17(1), 7231
06/06/2026
DOI: 10.1038/s41467-026-74058-0
PMID: 42251046
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.
Details
- Title: Subtitle
- IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2
- Creators
- Po Zhang - University of PittsburghWeichi Wu - University of North Carolina at Chapel HillTengfei Huang - University of North Carolina at Chapel HillXujia Wu - University of PittsburghDonghai Wang - University of North Carolina at Chapel HillHuairui Yuan - UPMC Hillman Cancer CenterSuchet Taori - University of PittsburghFanen Yuan - University of PittsburghFrank P Vendetti - UPMC Hillman Cancer CenterRui Wang - University of North Carolina at Chapel HillTingting Duan - University of PittsburghHailong Mi - University of PittsburghHuan Li - University of North Carolina at Chapel HillKailin Yang - University of IowaDaqi Li - University of North Carolina at Chapel HillAhmed Habib - University of PittsburghBriana C Prager - Massachusetts General HospitalRyan C Gimple - Washington University in St. LouisPascal O Zinn - University of PittsburghKalil Abdullah - UPMC Hillman Cancer CenterChristopher Bakkenist - UPMC Hillman Cancer CenterJunran Zhang - The Ohio State UniversityQiulian Wu - University of North Carolina at Chapel HillJeremy N Rich - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.17(1), 7231
- DOI
- 10.1038/s41467-026-74058-0
- PMID
- 42251046
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Nature
- Grant note
- NS136424 / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) CA238662 / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) CA268634 / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) NS134724 / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) CA283998 / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) HT9425-23-1-0689 / United States Department of Defense | Defense Health Agency (DHA) NS103434 / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
- Language
- English
- Electronic publication date
- 06/06/2026
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9985174609002771
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