title: RAB7 counteracts PI3K-driven macropinocytosis activated at early stages of melanoma development.
abstract: Derailed endolysosomal trafficking is emerging as a widespread feature of aggressive neoplasms. However, the oncogenic signals that alter membrane homeostasis and their specific contribution to cancer progression remain unclear. Understanding the upstream drivers and downstream regulators of aberrant vesicular trafficking is distinctly important in melanoma. This disease is notorious for its inter- and intra-tumoral heterogeneity. Nevertheless, melanomas uniformly overexpress a cluster of endolysosomal genes, being particularly addicted to the membrane traffic regulator RAB7. Still, the underlying mechanisms and temporal determinants of this dependency have yet to be defined. Here we addressed these questions by combining electron microscopy, real time imaging and mechanistic analyses of vesicular trafficking in normal and malignant human melanocytic cells. This strategy revealed Class I PI3K as the key trigger of a hyperactive influx of macropinosomes that melanoma cells counteract via RAB7-mediated lysosomal degradation. In addition, gain- and loss-of-function in vitro studies followed by histopathological validation in clinical biopsies and genetically-engineered mouse models, traced back the requirement of RAB7 to the suppression of premature cellular senescence traits elicited in melanocytes by PI3K-inducing oncogenes. Together, these results provide new insight into the regulators and modes of action of RAB7, broadening the impact of endosomal fitness on melanoma development.
authors.affiliation: Melanoma Laboratory, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.|Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Direna
authors.initials: D
authors.lastname: Alonso-Curbelo
authors.affiliation: Melanoma Laboratory, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Lisa
authors.initials: L
authors.lastname: Osterloh
authors.affiliation: Melanoma Laboratory, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Cañón
authors.affiliation: Melanoma Laboratory, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Tonantzin G
authors.initials: TG
authors.lastname: Calvo
authors.affiliation: Melanoma Laboratory, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Martínez-Herranz
authors.affiliation: Melanoma Laboratory, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Karras
authors.affiliation: Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez
authors.affiliation: Instituto de Investigación, Hospital 12 de Octubre Medical School, Universidad Complutense, Madrid, Spain.
authors.forename: Erica
authors.initials: E
authors.lastname: Riveiro-Falkenbach
authors.affiliation: Instituto de Investigación, Hospital 12 de Octubre Medical School, Universidad Complutense, Madrid, Spain.
authors.forename: Pablo-Ortiz
authors.initials: PO
authors.lastname: Romero
authors.affiliation: Instituto de Investigación, Hospital 12 de Octubre Medical School, Universidad Complutense, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Rodríguez-Peralto
authors.affiliation: Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pastor
authors.affiliation: Melanoma Laboratory, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: Soengas
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010873:Pinocytosis / Q000502:physiology*; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D020691:rab GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse
keywords: endosomes; macropinocytosis; oncogene-induced senescence; oncogenic stress; small GTPases