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

Karthic Swaminathan, Andrew Campbell, Vassilis Papalazarou, Farah Jaber-Hijazi, Colin Nixon, Ewan McGhee, Douglas Strathdee, Owen Sansom, Laura M. Machesky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
14 Downloads (Pure)

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. 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 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.

Original languageEnglish
Pages (from-to)628-637.e15
Number of pages25
JournalJournal of Investigative Dermatology
Volume141
Issue number3
Early online date8 Aug 2020
DOIs
Publication statusPublished - Mar 2021

Keywords

  • BRAF gene
  • melanoma
  • mouse model

Fingerprint

Dive into the research topics of 'The RAC1 target NCKAP1 plays a crucial role in progression of BRAF/PTEN -driven melanoma in mice'. Together they form a unique fingerprint.

Cite this