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

Madeline N. Hayes, Karin McCarthy, Alexander Jin, Mariana L. Oliveira, Sowmya Iyer, Sara P. Garcia, Sivasish Sindiri, Berkley Gryder, Zainab Motala, G. Petur Nielsen, Jean Paul Borg, Matt van de Rijn, David Malkin, Javed Khan, Myron S. Ignatius, David M. Langenau

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 for 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. Hayes et al. find that Vangl2 specifically labels progenitors that sustain growth and self-renewal in both zebrafish and human rhabdomyosarcoma and is required for their maintenance. This work reveals direct regulation of stem cell programs and tumor growth by Vangl2/RhoA signaling, offering opportunities for direct assessment and therapeutic targeting.

Original languageEnglish (US)
Pages (from-to)414-427.e6
JournalCell Stem Cell
Volume22
Issue number3
DOIs
StatePublished - Mar 1 2018

Keywords

  • RhoA
  • cancer
  • muscle
  • planar cell polarity
  • zebrafish

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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