LB33
P-Rex1 enhances Rac-dependent mesenchymal migration of human melanoma derived cell lines, and its loss inhibits melanocyte migration and metastasis formation in a mouse model of melanoma
Samuel Lawn1, Colin Lindsay1, William Faller1, Andrew Campbell1, Channing Der2, Kate Pedone2, Heidi Welch3, Lionel LaRue4, Ian Jackson5, Friedrich Beerman6, Owen Sansom1, Brad Ozanne1
1Beatson Institute for Cancer Research, Glasgow, UK; 2University of North Carolina, Chapel Hill, USA; 3Babraham Institute, Cambridge, UK; 4Institute Curie Centre de Recherche, Paris, France; 5MRC Human Genetics Unit, Edinburgh, UK; 6Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland
Background
P-Rex1, a Rac-specific guanine nucleotide exchange factor, is synergistically
activated by PIP3 and Gγ. Its MAPK-dependent expression is
up-regulated consistently in human melanoma derived cell lines, while human
melanocytes show no detectable expression. P-Rex1 enhances Rac-dependent
mesenchymal migration through matrigel. Most human melanomas have driver
mutations in either Nras or Braf.
Method
To investigate the role of P-Rex1 in melanoma formation and progression to
metastasis we used a mouse model of melanomagenesis driven by NrasQ61K
under the regulation of the tyrosinase promoter (Tyr-Nras) in which the CDKN2A
locus was deleted. These mice develop melanomas around 6 months and 30%
progress to lung or brain metastases.
Results
Interestingly, P-Rex1 is expressed in the melanocytes of Tyr-Nras mice but
not in melanocytes of Nras WT mice. The Tyr-Nras mice were then crossed to
either P-Rex1 WT or -/- mice. P-Rex1 -/- mice display a melanoblast migration
defect during development evidenced by a white belly stripe, which is
maintained in the presence of Tyr-Nras. Melanomas develop with similar
frequency and latency in Tyr-Nras mice regardless of the presence or absence of
P-Rex1; however progression to metastasis is dramatically suppressed in P-Rex1
-/- mice. Furthermore, immunohistochemical analysis has shown that P-Rex1 is
also expressed in human melanomas to varying degrees. We have also observed a
number of tumours in which high P-Rex1 expression is localised to the invading
front of the lesion.
Conclusion
We conclude that P-Rex1 plays an important role in melanocyte migration and
the progression of melanomas to metastases.
