<scp>W</scp>nt5<scp>A</scp> promotes an adaptive, senescent‐like stress response, while continuing to drive invasion in melanoma cells

Abstract

Abstract We have previously shown that W nt5 A drives invasion in melanoma. We have also shown that W nt5 A promotes resistance to therapy designed to target the BRAF V600E mutation in melanoma. Here, we show that melanomas characterized by high levels of W nt5 A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence‐associated β ‐galactosidase ( SA ‐ β ‐gal), senescence‐associated heterochromatic foci ( SAHF ), H 3 K 9 M e chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence such as SA ‐ β ‐gal and SAHF , these W nt5 A ‐high cells are able to colonize the lungs in in vivo tail vein colony‐forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing W nt5 A reduces expression of these markers and decreases invasiveness. The combined data point to W nt5 A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.