Abstract 2906: Role of autophagy in Wnt5A-mediated melanoma invasion and metastasis

Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease. With increasing incidence of the disease, it is crucial to further investigate the cellular mechanisms and molecular pathways that lead to invasion, metastasis, and drug resistance. Recent studies have revealed that high autophagy correlates with melanoma tumor aggressiveness and poor survival in clinical samples, as it is a common mechanism of resistance to therapy. Autophagy inhibition leads to reduced levels in Wnt5A in a breast cancer model, suggesting a cross-talk of Wnt5A and autophagy in cancer. β catenin, a mediator of canonical Wnt signaling, has been shown to act as a negative regulator of both basal and induced autophagy in a colorectal cancer model. Our laboratory showed that high levels of Wnt5A correlate with increased invasion and metastasis in melanoma and that Wnt5A downregulates β catenin; therefore, we hypothesize that autophagy might drive invasion and metastasis in aggressive melanoma through the regulation of Wnt signaling. To study the role of autophagy in Wnt5A-mediated melanoma invasion, we inhibited autophagy in highly invasive melanoma cells using lentivirus-mediated shATG5 knockdown or hydroxychloroquine and evaluated the effects of autophagy inhibition on Wnt5A expression, β catenin, and invasion using 3D spheroid models. Analysis of autophagy flux confirms that highly invasive melanoma cells have high autophagy compared to non-invasive cell lines. The inhibition of autophagy by hydroxychloroquine or shATG5 both resulted in significant decrease in invasion. By western blot analysis, we also observed a decrease in Wnt5A in these cells. These results demonstrate that autophagy inhibition in highly invasive melanoma leads to decrease in invasion in a 3D model that mimics the tumor microenvironment of melanoma. Further dissection of the molecular mechanisms that are involved in this process will enable the identification of novel autophagy targets in aggressive melanoma. Citation Format: Abibatou Ndoye, Anna Budina, Marie Webster, Amanpreet Kaur, Reeti Behera, Maureen Murphy, Ashani T. Weeraratna. Role of autophagy in Wnt5A-mediated melanoma invasion and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2906. doi:10.1158/1538-7445.AM2015-2906