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The RAC1 target NCKAP1 plays a crucial role in progression of BRAF/PTEN -driven melanoma in mice

; 
Campbell, A.
; 
Papalazarou, V.
; 
Jaber-Hijazi, F.
; 
Nixon, C.
; 
McGhee, E.
; 
Strathdee, D.
; 
Sansom, O.J.
; 
Machesky, L.M.
Publication Date
20201-03
End of Embargo
Supervisor
Keywords
Melanoma, Mice, RAC1
Rights
© 2021 Elsevier. Reproduced in accordance with the publisher's self-archiving policy. This manuscript version is made available under the CC-BY-NC-ND 4.0 license (https://creativecommons.org/licenses/by/4.0/)
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Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
2020-29-06
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Department
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Life Sciences Publications
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swaminathan_et_al_2020
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Abstract
BRAF V600E 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 BRAF V600E -driven melanoma progression and drug resistance. However, the underlying molecular mechanisms and the role of RAC1 downstream targets are not well explored. Here, 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 BRAF V600E; 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.
URI
http://hdl.handle.net/10454/18032
Version
Accepted manuscript
Citation
Swaminathan K, Campbell A, Papalazarou V et al (2021) The RAC1 target NCKAP1 plays a crucial role in progression of BRAF/PTEN -driven melanoma in mice. Journal of Investigative Dermatology. 141(3): 628-637.
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Link to Version of Record
https://doi.org/10.1016/j.jid.2020.06.029
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Article
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