Stroke Fuels Glioma Growth by Hijacking Astrocyte Calcium Signaling

Glioblastoma is the most common and aggressive malignant brain tumor in adults, with a dismal five-year survival rate, and its risk factors remain poorly understood. Clinical cohorts and case reports have linked ischemic stroke and traumatic brain injury to glioma. No study had tested whether stroke actually fuels tumor growth, or by what mechanism. This Nature Cancer study from Zhan and colleagues set out to establish causality and to identify the cellular machinery involved.

Transcriptome comparisons using The Cancer Genome Atlas showed that stroke and traumatic brain injury share gene signatures with high-grade glioma. The overlap involved hypoxia, inflammation and glial activation, and it was not seen in other neurodegenerative diseases. The team then induced photothrombotic stroke in mice before implanting patient-derived glioma stem-like cells. Stroke 7 or 28 days earlier increased tumor size, proliferation and cortical infiltration. In a second stroke model (middle cerebral artery occlusion), median survival fell from 66 to 60 days.

In an immunocompetent de novo model (Nf1, Trp53 and Pten deletion), stroke at postnatal day 28 cut median survival from 94 to 81 days. Whole-brain serial two-photon tomography showed greater infiltration in the isocortex and striatum, next to the lesion but not in the distant hippocampus, independent of tumor size. Single-cell and spatial transcriptomics revealed a proliferative, infiltrative tumor population resembling the leading edge of human glioblastoma. Fifteen genes were shared across high- and low-grade glioma models.

Tumor-associated astrocytes were the most altered microenvironment component. Stroke produced a distinct subpopulation with reduced normal astrocyte function and lower spontaneous calcium amplitude, frequency and area under the curve, most strongly near the lesion. Chemogenetic Gq activation of astrocytes (CNO 2.5 mg/kg twice daily) suppressed stroke-induced tumor expansion, infiltration and proliferation. Chronic activation extended median survival from 90 to 100 days without stroke (P=0.039), with a nonsignificant trend with stroke (79 versus 96 days, P=0.078). Microglia and macrophages were the second most remodeled group. Their depletion with PLX5622 reversed the stroke effect, with a stronger effect after stroke (interaction P=0.033).

The sodium bicarbonate cotransporter SLC4A4 was enriched in tumor-associated astrocytes in human gliomas and in about 75% of those in the mouse model. Overexpressing it restored calcium activity, shrank tumors and prolonged survival, while astrocyte-specific deletion worsened growth. Deleting Ccl2 or depleting microglia and macrophages abolished the harm from Slc4a4 loss. Stroke lowered Slc4a4 in stroke-induced tumor-associated astrocytes and produced extracellular acidosis (pHLIP probe) at postnatal day 60, partially reversed by overexpression.

The work is preclinical and mouse-based, so it shows a plausible mechanism rather than proof that stroke causes human glioma. Viral overexpression and chemogenetic stimulation are not yet clinical tools, and the survival benefit of chronic astrocyte activation after stroke was not statistically significant. The supplied text did not include the full limitations section, so conflicts of interest and further caveats could not be assessed. Still, the study points to astrocyte calcium signaling, the SLC4A4-CCL2 axis and microglia and macrophages as candidate targets.