Vangl2/RhoA 信号通路调控横纹肌肉瘤干细胞自我更新程序和生长。
Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma.
机构信息
Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02129, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02129, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
出版信息
Cell Stem Cell. 2018 Mar 1;22(3):414-427.e6. doi: 10.1016/j.stem.2018.02.002.
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.
肿瘤的生长和复发是由肿瘤增殖细胞（TPC）驱动的。然而，调节 TPC 命运选择、维持和自我更新的机制尚不完全清楚。在这里，我们表明，梵高样蛋白 2（Vangl2），非经典 Wnt/平面细胞极性（Wnt/PCP）途径的核心调节因子，影响横纹肌肉瘤（RMS）-一种肌肉的儿科癌症中的 TPC 自我更新。VANGL2 在大多数人类 RMS 和早期单核祖细胞中表达。VANGL2 耗竭抑制细胞增殖，减少 TPC 数量，并诱导体外和小鼠异种移植物中的人 RMS 分化。使用斑马鱼胚胎横纹肌肉瘤（ERMS）模型，我们确定 Vangl2 的表达富集 TPC 并促进其自我更新。RHOA 的组成性激活和显性失活异构体的表达表明，它在 VANGL2 下游作用，以调节人 RMS 中 TPC 的增殖和维持。我们的研究提供了控制 TPC 的途径的见解，并确定了新的潜在治疗靶点。
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