Cell Stem Cell: Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma

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Madeline N Hayes 1Karin McCarthy 1Alexander Jin 1Mariana L Oliveira 2Sowmya Iyer 1Sara P Garcia 1Sivasish Sindiri 3Berkley Gryder 3Zainab Motala 4G Petur Nielsen 5Jean-Paul Borg 6Matt van de Rijn 7David Malkin 4Javed Khan 3Myron S Ignatius 8David M Langenau 9

Abstract

Tumor growth and relapse are driven by tumor propagating cells (TPCs). However, mechanisms regulating TPC 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 (Wnt/PCP) pathway, affects TPC self-renewal in rhabdomyosarcoma (RMS)-a pediatric cancer of muscle. VANGL2 is expressed in a majority of human RMS and within early mononuclear progenitor cells. VANGL2 depletion inhibited cell proliferation, reduced TPC numbers, and induced differentiation of human RMS in vitro and in mouse xenografts. Using a zebrafish model of embryonal rhabdomyosarcoma (ERMS), we determined that Vangl2 expression enriches TPCs and promotes their self-renewal. Expression of constitutively active and dominant-negative isoforms of RHOA revealed that it acts downstream of VANGL2 to regulate proliferation and maintenance of TPCs in human RMS. Our studies offer insights into pathways that control TPCs and identify new potential therapeutic targets.

Keywords: RhoA; cancer; muscle; planar cell polarity; zebrafish.

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