The mechanoreceptor PIEZO1 is a novel oncogene in glioma by promoting astrocyte reactivity

Abstract

Glioblastoma is the most common and aggressive brain tumour in adults. Despite advances in its molecular characterization, there is a gap-of-knowledge in the identification of bona fide drivers and potential therapeutic targets that could change the clinical picture. Mechanoreception, the sensing of mechanical cues by cells, has proven to be an important factor in cell biology, particularly in cancer. Piezo1 is a mechanoreceptor found in all cells and seems to play a role in different cancer types, such as gastric, breast or lung cancer. However, there is still lack of understanding about its role in the onset and progression of glioblastoma. Here, we show that Piezo1 acts as an oncogene in glioma by potentially promoting chronic astrocyte reactivity. We developed a novel transgenic murine model of Piezo1 overexpression in astrocytes. These animals had a significant reduction in overall survival and developed glioma with a penetrance of 30%. We also developed a PIEZO1-overexpressing U251 cell line and found that it had a more aggressive and reactive-like phenotype. Finally, we correlated the levels of PIEZO1 with the clinical outcome of a cohort of glioblastoma patients and observed that PIEZO1 is a biomarker of worse prognosis. However, PIEZO1 only correlated with worse prognosis in male patients, suggesting a sexual dimorphism. In conclusion, we identified Piezo1 as a bona fide driver of glioma, revealing its implication in astrocyte reactivity and identifying it as a biomarker for glioma in the clinic.