Senescence is a cytostatic cell fate that can be induced by oncogene activation, replicative stress or therapy-induced stress. Therapy-induced senescence (TIS) of tumor cells can be initiated by anti-cancer compounds or radiation. TIS is generally considered to be irreversible, and as such this process is believed to be a desirable therapeutic outcome. In this study, we show that melanomas characterized by high levels of the signaling molecule Wnt5A respond to irradiation by undergoing growth arrest, and by expressing classical markers of senescence, including positivity for senescence-associated beta-galactosidase (SA-β-gal), senescence associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. Even though these cells are positive for classical markers of senescence, we find that they retain their ability to migrate and invade. Further, these Wnt5A-high cells are able to proliferate following metastasis and form new tumors in the lung, while expressing increased markers of senescence. Silencing Wnt5A reduces expression of these senescence markers and decreases invasiveness. Finally, Wnt5A-high melanoma cells treated with PLX4720, a BRAFV600E targeted therapy, also increase markers of a TIS response, while remaining invasive. The combined data challenge the paradigm that TIS is a desirable therapeutic endpoint. They also point to Wnt5A as a master regulator of this senescence-like stress-induced phenotype in melanoma.
Citation Format: Marie R. Webster, Mai Xu, Kathryn Kinzler, Amanpreet Kaur, Jessica Appleton, Michael P. O'Connell, Katie Marchbank, Alexander Valiga, Vanessa Dang, Michela Perego, Gao Zhang, Ana Slipicevic, Frederick Keeney, Elin Lehrmann, William Wood, III, Kevin Becker, Andrew V. Kossenkov, Meenhard Herlyn, Maureen Murphy, Ashani T. Weeraratna. Wnt5A-expressing melanoma cells show classical markers of senescence following radiation and therapeutic stress, but retain the ability to metastasize and proliferate at distant sites. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B27.