@article{2ed0c194410d424eafd7d1fee5d34474,
title = "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. 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.",
keywords = "RhoA, cancer, muscle, planar cell polarity, zebrafish",
author = "Hayes, {Madeline N.} and Karin McCarthy and Alexander Jin and Oliveira, {Mariana L.} and Sowmya Iyer and Garcia, {Sara P.} and Sivasish Sindiri and Berkley Gryder and Zainab Motala and Nielsen, {G. Petur} and Borg, {Jean Paul} and {van de Rijn}, Matt and David Malkin and Javed Khan and Ignatius, {Myron S.} and Langenau, {David M.}",
note = "Funding Information: This work was funded by NIH grants R01CA154923 (D.M.L.), R01CA215118 (D.M.L.), R24OD016761 (D.M.L.), and U54CA168512 (D.M.L.); a St. Baldricks Research Grant (D.M.L.); the MGH Scholars Program (D.M.L.); the Alex's Lemonade Stand Foundation (M.N.H.); and the Amanda Riley Foundation (M.N.H., Bear Necessities). We thank the Specialized Histopathology Services at Massachusetts General Hospital (MGH) and the Dana-Farber/Harvard Cancer Center (P30 CA06516), the MGH Cancer Center/Molecular Pathology Confocal Core, and the MGH CNY Flow Cytometry Core and Flow Image Analysis (1S10RR023440-01A1). The work of Z.M. and D.M. was supported through a Rhabdomyosarcoma Research Fund from SickKids Foundation. The work of M.I. was supported by NIH grant R00CA175184. Funding Information: This work was funded by NIH grants R01CA154923 (D.M.L.), R01CA215118 (D.M.L.), R24OD016761 (D.M.L.), and U54CA168512 (D.M.L.); a St. Baldricks Research Grant (D.M.L.); the MGH Scholars Program (D.M.L.); the Alex{\textquoteright}s Lemonade Stand Foundation (M.N.H.); and the Amanda Riley Foundation (M.N.H., Bear Necessities). We thank the Specialized Histopathology Services at Massachusetts General Hospital (MGH ) and the Dana-Farber/Harvard Cancer Center ( P30 CA06516 ), the MGH Cancer Center/Molecular Pathology Confocal Core , and the MGH CNY Flow Cytometry Core and Flow Image Analysis ( 1S10RR023440-01A1 ). The work of Z.M. and D.M. was supported through a Rhabdomyosarcoma Research Fund from SickKids Foundation . The work of M.I. was supported by NIH grant R00CA175184 . Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = mar,
day = "1",
doi = "10.1016/j.stem.2018.02.002",
language = "English (US)",
volume = "22",
pages = "414--427.e6",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "3",
}