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

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.

tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish

“…Unexpectedly, kRAS G12D -induced tumors harboring wild-type tp53 had similar frequency of tumor-propagating stem cells when compared with those of tp53 del/del ERMS (n ≥ 3 tumors analyzed per genotype, p=0.647 EDLA analysis, Table 1 ). We concluded that Tp53 loss-of-function does not alter the overall frequency of tumor-sustaining, cancer stem cells in ERMS, which contrasts with previous studies that defined major roles for NOTCH1, MYF5/MYOD, and WNT signaling in regulating self-renewal and the overall number of tumor sustaining cell types in rhabdomyosarcoma ( Chen et al, 2014 ; Hayes et al, 2018 ; Ignatius et al, 2017 ; Tenente et al, 2017 ).…”

Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors

“…These, so-called, noncanonical Wnt signalling pathways are highly conserved from Drosophila through to vertebrates and utilise a broad range of cell surface receptors to activate diverse downstream processes [18][19][20] . Wnt-Planar Cell Polarity (Wnt-PCP) signalling represents one of these non-canonical pathways and is required for a number of morphogenic processes in the embryo; 21,22 moreover, Wnt-PCP signalling has been implicated in the pathogenesis of a number of adult diseases and cancers [23][24][25] . Whether Wnt-PCP signalling plays a role in bile duct disease and regeneration has not been determined.…”

PROX1 transcription factor is a master regulator of myogenic and oncogenic features of rhabdomyosarcoma

“…From the RNAseq data, we analyzed the expression of the oncogenes that have previously been shown to be upregulated, and characterized as tumorigenic, in RMS. Several such genes were found to be significantly repressed by PROX1 silencing: FGFR4, MYL4 (Khan et al, 2001), IGFBP5, IGF2 (El-Badry et al, 1990; Khan et al, 1999), MYOG (Gryder et al, 2017), MYCN (Williamson et al, 2005), RASSF4 (Crose et al, 2014), VANGL2 (Hayes et al, 2018), Hey1 (Belyea et al, 2011) and NOTCH3 (De Salvo et al, 2014) ( Figure 5A ). Correlation analysis of these genes with PROX1 using RMS tumor RNA expression data in MediSapiens (n = 49 tumors, http://ist.medisapiens.com/) showed significant correlation between PROX1 and six of these genes ( Supplement Figure 3 ), of which one of the strongest correlations was found between PROX1 and FGFR4 ( Figure 5B ).…”