Abstract 3171: Vangl2 regulates cancer stem cell self-renewal and growth in rhabdomyosarcoma

Growth and relapse are driven by cancer stem cells (CSCs) in a subset of tumors, yet mechanisms driving cancer cell fate choices, maintenance and self-renewal are not fully understood. Here, we show that Van Gogh-like 2 (Vangl2), a core regulator of the non-canonical Wnt/planar cell polarity pathway (Wnt/PCP), regulates CSCs self-renewal in human rhabdomyosarcoma (RMS) – a common pediatric cancer of muscle. Wnt/PCP signaling is essential during development and recent work has linked this pathway to cancer growth, invasion and metastasis. However, roles for Vangl2 in regulating tumor self-renewal have not been previously described. Here, we show that VANGL2 is expressed in a majority of human RMS, specifically within early mononuclear progenitor-like cells. VANGL2 depletion inhibited proliferation, reduced self-renewal, and induced differentiation of human RMS. VANGL2 was also required for continued tumor growth and maintenance following engraftment of human RMS using mouse xenografts. Using a zebrafish model of embryonal rhabdomyosarcoma (ERMS) and limiting dilution cell transplantation approaches, we identified that Vangl2 expression enriches for CSCs in vivo and when transgenically expressed, at high levels elevates cancer stem cell number by 9-fold. Mechanistic studies revealed a role for RhoA downstream of Vangl2 in regulating maintenance of stem cell programs in human RMS. Our studies offer novel opportunities to isolate and characterize RMS cancer stem cells in vivo, and identify potential therapeutic targets for patient treatment. Citation Format: Madeline Hayes, Karin McCarthy, Alexander Jin, Sowmya Iyer, Sara Garcia, Mariana L. Oliveira, Sivasish Sindiri, Berkley Gryder, Zainab Motala, G Petur Nielsen, Jean-Paul Borg, Matt van de Rijn, David Malkin, Javed Khan, Myron Ignatius, David M. Langenau. Vangl2 regulates cancer stem cell self-renewal and growth in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3171.