RAC1 P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance.

Autor:	Lionarons DA; Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Hancock DC; Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Rana S; Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Lung Cancer Group, Division of Molecular Pathology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK., East P; Bioinformatics & Biostatistics, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Moore C; Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Murillo MM; Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Lung Cancer Group, Division of Molecular Pathology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK., Carvalho J; Experimental Histopathology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Spencer-Dene B; Experimental Histopathology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Herbert E; Experimental Histopathology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Royal Veterinary College, Hatfield AL9 7TA, UK., Stamp G; Experimental Histopathology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Damry D; Immunity & Cancer Laboratories, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Calado DP; Immunity & Cancer Laboratories, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Rosewell I; Genetic Manipulation Service, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Fritsch R; Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Universitätsklinikum Freiburg, Freiburg 79106, Germany., Neubig RR; Michigan State University, East Lansing, MI 48824, USA., Molina-Arcas M; Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: miriam.molina@crick.ac.uk., Downward J; Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Lung Cancer Group, Division of Molecular Pathology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. Electronic address: julian.downward@crick.ac.uk.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2019 Jul 08; Vol. 36 (1), pp. 68-83.e9. Date of Electronic Publication: 2019 Jun 27.
DOI:	10.1016/j.ccell.2019.05.015
Abstrakt:	RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1 P29S in melanoma development and reveal that RAC1 P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1 P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1 P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1 P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1 P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target. (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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