title: CRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch-Dependent Signaling.
abstract: 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 neurologic 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 GBM 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 have shown 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 GBM that correlates with and may predict patient survival.
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Aubin
authors.initials: A
authors.lastname: Moutal
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Massoma
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Désormeaux
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bertrand
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Malleval
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Watrin
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Naura
authors.initials: N
authors.lastname: Chounlamountri
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Mayeur
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Besançon
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Naudet
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Magadoux
authors.affiliation: Department of Pharmacology and Neuroscience Graduate Interdisciplinary Program, College of Medicine, University of Arizona, Tucson, Arizona.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France. Hospices Civils de Lyon, Neuro-Oncology, Lyon, France.
authors.forename: François
authors.initials: F
authors.lastname: Ducray
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France. Hospices Civils de Lyon, Centre de Pathologie et de Neuropathologie Est, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Meyronet
authors.affiliation: INSERM U1028, CNRS UM5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, University Claude Bernard Lyon 1, Lyon, France. nicole.thomasset@inserm.fr.
authors.forename: Nicole
authors.initials: N
authors.lastname: Thomasset
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D006867:Hydrolases; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; C415087:DPYSL5 protein, human; D006867:Hydrolases