The RAC1 target NCKAP1 plays a crucial role in the progression of Braf;Pten-driven melanoma in mice

Swaminathan, K., Campbell, A., Papalazarou, V., Jaber-Hijazi, F. , Nixon, C., McGhee, E., Strathdee, D., Sansom, O. J. and Machesky, L. M. (2021) The RAC1 target NCKAP1 plays a crucial role in the progression of Braf;Pten-driven melanoma in mice. Journal of Investigative Dermatology, 141(3), 628-637.e15. (doi: 10.1016/j.jid.2020.06.029) (PMID:32777214)

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Abstract

BRAFV600E is the most common driver mutation in human cutaneous melanoma and is frequently accompanied by loss of the tumor-suppressing phosphatase PTEN. Recent evidence suggests a co-operative role for RAC1 activity in BRAFV600E-driven melanoma progression and drug resistance. However, the underlying molecular mechanisms and the role of RAC1 downstream targets are not well-explored. In this study, we examine the role of the NCKAP1 subunit of the pentameric cytoskeletal SCAR/WAVE complex, a major downstream target of RAC1, in a mouse model of melanoma driven by BRAFV600E;PTEN loss. The SCAR/WAVE complex is the major driver of lamellipodia formation and cell migration downstream of RAC1 and depends on NCKAP1 for its integrity. Targeted deletion of Nckap1 in the melanocyte lineage delayed tumor onset and progression of a mutant Braf;Pten loss‒driven melanoma mouse model. Nckap1-depleted tumors displayed fibrotic stroma with increased collagen deposition concomitant with enhanced immune infiltration. Nckap1 loss slowed proliferation and tumor growth, highlighting a role in cell-cycle progression. Altogether, we propose that NCKAP1-orchestrated actin polymerization is essential for tumor progression and maintenance of tumor tissue integrity in a mutant Braf/Pten loss‒driven mouse model for melanoma.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jaber, Dr Farah and Nixon, Mr Colin and McGhee, Dr Ewan and Machesky, Professor Laura and Papalazarou, Mr Vasileios and Strathdee, Dr Douglas and Sansom, Professor Owen and Campbell, Dr Andrew
Authors: Swaminathan, K., Campbell, A., Papalazarou, V., Jaber-Hijazi, F., Nixon, C., McGhee, E., Strathdee, D., Sansom, O. J., and Machesky, L. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Science and Engineering > School of Engineering
Journal Name:Journal of Investigative Dermatology
Publisher:Elsevier
ISSN:0022-202X
ISSN (Online):1523-1747
Published Online:08 August 2020

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research