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RAC1$^{P29S}$ induces a mesenchymal phenotypic switch via serum response factor to promote melanoma development and therapy resistance


Lionarons, Daniël A; Hancock, David C; Rana, Sareena; East, Philip; Moore, Christopher; Murillo, Miguel M; Carvalho, Joana; Spencer-Dene, Bradley; Herbert, Eleanor; Stamp, Gordon; Damry, Djamil; Calado, Dinis P; Rosewell, Ian; Fritsch, Ralph; Neubig, Richard R; Molina-Arcas, Miriam; Downward, Julian (2019). RAC1$^{P29S}$ induces a mesenchymal phenotypic switch via serum response factor to promote melanoma development and therapy resistance. Cancer Cell, 36(1):68-83.e9.

Abstract

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.

Abstract

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology and Hematology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Oncology
Life Sciences > Cell Biology
Life Sciences > Cancer Research
Language:English
Date:8 July 2019
Deposited On:13 Feb 2020 16:45
Last Modified:29 Jul 2020 14:23
Publisher:Cell Press (Elsevier)
ISSN:1535-6108
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.ccell.2019.05.015
PubMed ID:31257073

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