Webster Marie R, Xu Mai, Kinzler Kathryn A, Kaur Amanpreet, Appleton Jessica, O'Connell Michael P, Marchbank Katie, Valiga Alexander, Dang Vanessa M, Perego Michela, Zhang Gao, Slipicevic Ana, Keeney Frederick, Lehrmann Elin, Wood William, Becker Kevin G, Kossenkov Andrew V, Frederick Dennie T, Flaherty Keith T, Xu Xiaowei, Herlyn Meenhard, Murphy Maureen E, Weeraratna Ashani T
The Wistar Institute, Philadelphia, PA, USA.
Pigment Cell Melanoma Res. 2015 Mar;28(2):184-95. doi: 10.1111/pcmr.12330. Epub 2014 Dec 29.
We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A 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), H3K9Me 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 Wnt5A-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 Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.
我们之前已经表明，Wnt5A会促使黑色素瘤发生侵袭。我们还表明，Wnt5A会增强黑色素瘤对针对BRAF（V600E）突变的治疗的抗性。在此，我们表明，以高水平Wnt5A为特征的黑色素瘤通过增加p21并表达衰老的经典标志物来应对治疗应激，这些标志物包括衰老相关β-半乳糖苷酶（SA-β-gal）呈阳性、衰老相关异染色质灶（SAHF）、H3K9Me染色质标记以及早幼粒细胞白血病蛋白（PML）小体。我们发现，尽管如此，这些细胞仍保留其迁移和侵袭能力。此外，尽管表达了SA-β-gal和SAHF等衰老经典标志物，但这些高Wnt5A细胞在体内尾静脉集落形成试验中仍能够在肺部形成集落。这清楚地强调了一个事实，即这些标志物并不表明这些细胞发生了真正的衰老，而是一种适应性应激反应，使细胞能够逃避治疗并发生侵袭。值得注意的是，沉默Wnt5A会降低这些标志物的表达并降低侵袭性。综合数据表明，Wnt5A是黑色素瘤适应性应激反应的主要调节因子，这可能导致治疗抗性。
