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

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. In glioblastoma, matrix stiffness has been linked to poor prognosis and resistance to therapy. Here, the authors demonstrate that matrix stiffness drives radioresistance via upregulation of IQGAP3 promoting cancer cell stemness via SOX2 stabilization and show that blocking this interaction resensitises glioblastoma cells to radiotherapy.