N-WASP control of LPAR1 trafficking establishes response to self-generated LPA gradients to promote pancreatic cancer cell metastasis
| Autor: | Ewan J. McGhee, Kirsty J. Martin, Laura M. Machesky, Sergio Lilla, Nikolaj Gadegaard, Gabriela Kalna, Jim C. Norman, Peter A. Thomason, Yvette W. H. Koh, Gillian M. Mackay, Matthew Neilson, Heather J. Spence, Amelie Juin, Robert H. Insall, Loic Fort, Marie F.A. Cutiongco |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Receptor recycling RHOA Mice Nude Wiskott-Aldrich Syndrome Protein Neuronal Biology General Biochemistry Genetics and Molecular Biology Metastasis Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Movement Cell Line Tumor Pancreatic cancer Lysophosphatidic acid medicine Animals Humans Neoplasm Invasiveness Neoplasm Metastasis Receptors Lysophosphatidic Acid Sorting Nexins Molecular Biology 030304 developmental biology 0303 health sciences LPAR1 Chemotaxis Cell migration Cell Biology medicine.disease Rats 3. Good health Pancreatic Neoplasms Protein Transport chemistry Cancer cell biology.protein Cancer research Female Lysophospholipids rhoA GTP-Binding Protein 030217 neurology & neurosurgery Carcinoma Pancreatic Ductal Signal Transduction Developmental Biology |
| Zdroj: | Cutiongco, M 2019, ' N-WASP Control of LPAR1 Trafficking Establishes Response to Self-Generated LPA Gradients to Promote Pancreatic Cancer Cell Metastasis ', Developmental cell . https://doi.org/10.1016/j.devcel.2019.09.018 |
| ISSN: | 1534-5807 |
| Popis: | Pancreatic ductal adenocarcinoma is one of the most invasive and metastatic cancers and has a dismal 5-year survival rate. We show that N-WASP drives pancreatic cancer metastasis, with roles in both chemotaxis and matrix remodeling. lysophosphatidic acid, a signaling lipid abundant in blood and ascites fluid, is both a mitogen and chemoattractant for cancer cells. Pancreatic cancer cells break lysophosphatidic acid down as they respond to it, setting up a self-generated gradient driving tumor egress. N-WASP-depleted cells do not recognize lysophosphatidic acid gradients, leading to altered RhoA activation, decreased contractility and traction forces, and reduced metastasis. We describe a signaling loop whereby N-WASP and the endocytic adapter SNX18 promote lysophosphatidic acid-induced RhoA-mediated contractility and force generation by controlling lysophosphatidic acid receptor recycling and preventing degradation. This chemotactic loop drives collagen remodeling, tumor invasion, and metastasis and could be an important target against pancreatic cancer spread. |
| Databáze: | OpenAIRE |
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