Stroke drives glioma progression through the emergence of tumor-associated astrocytes with reduced Ca2+ activity

Abstract

Epidemiological studies suggest that persons with a history of stroke are at increased risk of developing brain tumors, yet the mechanisms linking brain injury to glioma progression remain unclear. Here we show that stroke promotes tumor infiltration into injured brain regions in human and mouse glioma models, accompanied by reduced overall survival. Stroke induces remodeling of the tumor microenvironment, including the emergence of a distinct population of tumor-associated astrocytes (TAAs) with diminished Ca2+ activity at the invasive front and enrichment of tumor-associated microglia and macrophages (TAMs). Restoring TAA Ca2+ signaling or TAM depletion suppresses stroke-induced glioma progression, identifying both populations as critical mediators of the injury response. Mechanistically, we identified SLC4A4 as a key regulator of Ca2+ activity in TAAs and CCL2-mediated TAM recruitment. Collectively, our findings establish stroke-induced remodeling of astrocytic Ca2+ signaling and TAMs as drivers of glioma progression and link brain injury to malignant disease. Lee and colleagues report that ischemic stroke induces the generation of an astrocytic population that, through reduced calcium signaling, favors the recruitment of tumor-associated macrophages, thereby promoting glioma invasion in preclinical models.