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

Cell Stem Cell. 2018 Mar 1;22(3):414-427.e6. doi: 10.1016/j.stem.2018.02.002.

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Self Renewal*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Monomeric GTP-Binding Proteins / metabolism*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Rhabdomyosarcoma / genetics
  • Rhabdomyosarcoma / pathology*
  • Signal Transduction*
  • Xenograft Model Antitumor Assays
  • Zebrafish Proteins / metabolism*
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • VANGL2 protein, human
  • Zebrafish Proteins
  • vangl2 protein, zebrafish
  • RHOA protein, human
  • Monomeric GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • rhoab protein, zebrafish