CRTAC1-A reprograms extracellular matrix viscoelasticity to constrain glioma progression

Abstract

Mechanical remodeling of the extracellular matrix (ECM) influences glioma progression, yet the molecular regulators that control tumor matrix mechanics remain poorly understood. By comparing low-grade gliomas (LGGs), associated with improved patient survival, with glioblastomas (GBMs), which carry a poor prognosis, we identified the cartilage-derived ECM protein CRTAC1-A as enriched in LGGs and significantly reduced in GBMs, with elevated expression correlating with improved patient survival. Restoration of CRTAC1-A suppressed glioma cell proliferation and invasion and enhanced temozolomide efficacy in three-dimensional tumor spheroid models. Mechanistically, CRTAC1-A directly interacts with collagen I and reorganizes collagen networks across multiple length scales, generating a mechanically compliant yet structurally resilient ECM with reduced stiffness, enhanced elastic recovery, and resistance to persistent remodeling. This viscoelastic normalization limits invasive remodeling while preserving matrix permeability and drug penetration. Together, these findings identify CRTAC1-A as a reversible regulator of tumor ECM mechanics that suppresses glioma malignancy.