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

被引：58

作者：

Hayes, Madeline N. ^{[1
,2
,3
]}

McCarthy, Karin ^{[1
,2
,3
]}

Jin, Alexander ^{[1
,2
,3
]}

Oliveira, Mariana L. ^{[1
,2
,3
,4
]}

Iyer, Sowmya ^{[1
,2
,3
]}

Garcia, Sara P. ^{[1
,2
,3
]}

Sindiri, Sivasish ^{[5
]}

Gryder, Berkley ^{[5
]}

Motala, Zainab ^{[6
,7
]}

Nielsen, G. Petur ^{[8
]}

Borg, Jean-Paul ^{[9
]}

De Rijn, Matt Van ^{[10
]}

Malkin, David ^{[6
,7
]}

Khan, Javed ^{[5
]}

Ignatius, Myron S. ^{[11
,12
]}

Langenau, David M. ^{[1
,2
,3
]}

机构：

[1] Massachusetts Gen Hosp, Res Inst, Ctr Canc, Mol Pathol, Boston, MA 02129 USA

[2] Massachusetts Gen Hosp, Res Inst, Regenerat Med, Boston, MA 02129 USA

[3] Harvard Stem Cell Inst, Cambridge, MA 02139 USA

[4] Univ Lisbon, Fac Med, Inst Med Mol, P-1649028 Lisbon, Portugal

[5] NCI, Oncogen Sect, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA

[6] Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada

[7] Univ Toronto, Dept Pediat, Toronto, ON M5G 1X8, Canada

[8] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA

[9] Aix Marseille Univ UM105, Ctr Rech Cancerol Marseille, Equipe Labellise Ligue Canc,CNRS UMR7258,INSERM U, Inst Paoli Calmettes,Cell Polar Cell Signalling &, Marseille, France

[10] Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA

[11] UTHSCSA, Mol Med, San Antonio, TX 78229 USA

[12] UTHSCSA, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA

来源：

CELL STEM CELL | 2018年 / 22卷 / 03期

关键词：

POLARITY; EXPRESSION; MUSCLE; CANCER; MIGRATION; GENE; DIFFERENTIATION; PROLIFERATION; MECHANISMS; MOVEMENTS;

D O I：

10.1016/j.stem.2018.02.002

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：414 / +

页数：20

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