RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

Daniël A Lionarons; David C Hancock; Sareena Rana; Philip East; Christopher Moore; Miguel M Murillo; Joana Carvalho; Bradley Spencer-Dene; Eleanor Herbert; Gordon Stamp; Djamil Damry; Dinis P Calado; Ian Rosewell; Ralph Fritsch; Richard R Neubig; Miriam Molina-Arcas; Julian Downward

doi:https://doi.org/10.1016/j.ccell.2019.05.015

RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

Daniël A Lionarons, David C Hancock, Sareena Rana, Philip East, Christopher Moore, Miguel M Murillo, Joana Carvalho, Bradley Spencer-Dene, Eleanor Herbert, Gordon Stamp, Djamil Damry, Dinis P Calado, Ian Rosewell, Ralph Fritsch, Richard R Neubig, Miriam Molina-Arcas, Julian Downward

Research output: Contribution to journal › Article › Academic › peer-review

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 RAC1P29S in melanoma development and reveal that RAC1P29S 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 RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.

Original language	English
Pages (from-to)	68-83.e9
Journal	Cancer cell
Volume	36
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2019.05.015
Publication status	Published - 8 Jul 2019

Keywords

Alleles
Amino Acid Substitution
Animals
Cell Line, Tumor
Cell Survival/drug effects
Cell Transformation, Neoplastic/genetics
Disease Models, Animal
Drug Resistance, Neoplasm/genetics
Epithelial-Mesenchymal Transition/genetics
Female
Gene Expression
Humans
Male
Melanocytes/metabolism
Melanoma/etiology
Mice
Mice, Transgenic
Models, Biological
Mutation
Prognosis
Protein Kinase Inhibitors/pharmacology
Proto-Oncogene Proteins B-raf/genetics
Serum Response Factor
Xenograft Model Antitumor Assays
rac1 GTP-Binding Protein/genetics

Access to Document

https://doi.org/10.1016/j.ccell.2019.05.015

Cite this

Lionarons, D. A., Hancock, D. C., Rana, S., East, P., Moore, C., Murillo, M. M., Carvalho, J., Spencer-Dene, B., Herbert, E., Stamp, G., Damry, D., Calado, D. P., Rosewell, I., Fritsch, R., Neubig, R. R., Molina-Arcas, M., & Downward, J. (2019). RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance. Cancer cell, 36(1), 68-83.e9. https://doi.org/10.1016/j.ccell.2019.05.015

@article{2bd8fa07af26496292240796caead683,

title = "RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance",

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 RAC1P29S in melanoma development and reveal that RAC1P29S 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 RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.",

keywords = "Alleles, Amino Acid Substitution, Animals, Cell Line, Tumor, Cell Survival/drug effects, Cell Transformation, Neoplastic/genetics, Disease Models, Animal, Drug Resistance, Neoplasm/genetics, Epithelial-Mesenchymal Transition/genetics, Female, Gene Expression, Humans, Male, Melanocytes/metabolism, Melanoma/etiology, Mice, Mice, Transgenic, Models, Biological, Mutation, Prognosis, Protein Kinase Inhibitors/pharmacology, Proto-Oncogene Proteins B-raf/genetics, Serum Response Factor, Xenograft Model Antitumor Assays, rac1 GTP-Binding Protein/genetics",

author = "Lionarons, {Dani{\"e}l A} and Hancock, {David C} and Sareena Rana and Philip East and Christopher Moore and Murillo, {Miguel M} and Joana Carvalho and Bradley Spencer-Dene and Eleanor Herbert and Gordon Stamp and Djamil Damry and Calado, {Dinis P} and Ian Rosewell and Ralph Fritsch and Neubig, {Richard R} and Miriam Molina-Arcas and Julian Downward",

year = "2019",

month = jul,

day = "8",

doi = "https://doi.org/10.1016/j.ccell.2019.05.015",

language = "English",

volume = "36",

pages = "68--83.e9",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "1",

}

Lionarons, DA, Hancock, DC, Rana, S, East, P, Moore, C, Murillo, MM, Carvalho, J, Spencer-Dene, B, Herbert, E, Stamp, G, Damry, D, Calado, DP, Rosewell, I, Fritsch, R, Neubig, RR, Molina-Arcas, M & Downward, J 2019, 'RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance', Cancer cell, vol. 36, no. 1, pp. 68-83.e9. https://doi.org/10.1016/j.ccell.2019.05.015

TY - JOUR

T1 - RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

AU - Lionarons, Daniël A

AU - Hancock, David C

AU - Rana, Sareena

AU - East, Philip

AU - Moore, Christopher

AU - Murillo, Miguel M

AU - Carvalho, Joana

AU - Spencer-Dene, Bradley

AU - Herbert, Eleanor

AU - Stamp, Gordon

AU - Damry, Djamil

AU - Calado, Dinis P

AU - Rosewell, Ian

AU - Fritsch, Ralph

AU - Neubig, Richard R

AU - Molina-Arcas, Miriam

AU - Downward, Julian

PY - 2019/7/8

Y1 - 2019/7/8

N2 - 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 RAC1P29S in melanoma development and reveal that RAC1P29S 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 RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.

AB - 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 RAC1P29S in melanoma development and reveal that RAC1P29S 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 RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.

KW - Alleles

KW - Amino Acid Substitution

KW - Animals

KW - Cell Line, Tumor

KW - Cell Survival/drug effects

KW - Cell Transformation, Neoplastic/genetics

KW - Disease Models, Animal

KW - Drug Resistance, Neoplasm/genetics

KW - Epithelial-Mesenchymal Transition/genetics

KW - Female

KW - Gene Expression

KW - Humans

KW - Male

KW - Melanocytes/metabolism

KW - Melanoma/etiology

KW - Mice

KW - Mice, Transgenic

KW - Models, Biological

KW - Mutation

KW - Prognosis

KW - Protein Kinase Inhibitors/pharmacology

KW - Proto-Oncogene Proteins B-raf/genetics

KW - Serum Response Factor

KW - Xenograft Model Antitumor Assays

KW - rac1 GTP-Binding Protein/genetics

U2 - https://doi.org/10.1016/j.ccell.2019.05.015

DO - https://doi.org/10.1016/j.ccell.2019.05.015

M3 - Article

C2 - 31257073

SN - 1535-6108

VL - 36

SP - 68-83.e9

JO - Cancer cell

JF - Cancer cell

IS - 1

ER -