CRMP5 controls glioblastoma cell proliferation and survival through Notch-dependent signaling
Menée in vitro et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, cette étude met en évidence des mécanismes par lesquels, via la signalisation Notch et l'activation du gène Akt, la protéine CRMP5 régule la prolifération des cellules cancéreuses
Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that play a major role in nervous system development. This protein was first described in cancer-induced autoimmune processes, causing neurodegenerative disorders (paraneoplastic neurological syndromes). CRMP5 expression has been reported to serve as a biomarker for high-grade lung neuroendocrine carcinomas, however, its functional roles have not been examined in any setting of cancer pathophysiology. In this study, we report two different CRMP5 expression patterns observed in human glioblastoma (GBM) biopsies that establish connections between CRMP5 expression, Notch receptor signaling and glioblastoma cell proliferation. We demonstrated that elevated CRMP5 promotes Notch receptor expression and Akt activation in human tumor cell lines,GBM_stem cells and primary tumor biopsies. We showed that the high CRMP5 and Notch expression in GBM xenograft is related to stem cells. This suggests that high CRMP5 expression pattern in GBM biopsies encompasses a subset of stem cells. Mechanistically, CRMP5 functioned by hijacking Notch receptors from Itch-dependent lysosomal degradation. Our findings suggest that CRMP5 serves as a major mediator of Notch signaling and Akt activation by controlling the degradation of the Notch receptor, with implications for defining a biomarker signature in glioblastoma that correlates with and may predict patient survival.