PAX3-FOXO1融合基因减少横纹肌肉瘤中的细胞-细胞外基质相互作用和转化生长因子β信号传导。

The PAX3-FOXO1 fusion gene reduces cell-ECM interactions and TGFβ signaling in rhabdomyosarcoma.

作者信息

Chronopoulos Antonios, Chavez Ivan, Vemula Chandra Kaladhar, Mittal Nikhil, Zamloot Vic, Pan Yuanzhong, Han Sangyoon J, Park JinSeok

机构信息

Cancer and Blood Disease Institute, Children's Hospital Los Angeles , Los Angeles, CA, USA.

Department of Biomedical Engineering, Michigan Technological University, Houghton, MI, USA.

出版信息

J Cell Biol. 2025 Jul 7;224(7). doi: 10.1083/jcb.202408155. Epub 2025 Jun 30.

DOI:10.1083/jcb.202408155

PMID:40586712

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12207912/

Abstract

We identify downregulation of genes related to cell-ECM interactions and TGFβ signaling in FPRMS. We confirm that TGFβ signaling enhances cell-ECM interactions in FNRMS, utilizing confocal reflection microscopy to assess ECM remodeling, and a live-cell sensor to quantitatively assess TGFβ signaling. We also show that PAX3-FOXO1 increases NOS1 expression, stimulating nitric oxide synthesis, which inhibits TGFβ signaling and reduces cell-ECM interactions. We suggest that PAX3-FOXO1 reprograms ECM anchorage dependence by suppressing cell-ECM interactions. The fusion gene can determine sensitivity to growth inhibition via targeted disruption of cell-ECM interactions or TGFβ signaling. Reduced anchorage reliance by the gene may allow cells to survive in circulation and enhance FPRMS metastatic potential.

摘要

我们确定了与纤维母细胞型横纹肌肉瘤（FPRMS）中细胞与细胞外基质（ECM）相互作用及转化生长因子β（TGFβ）信号传导相关的基因下调。我们证实，利用共聚焦反射显微镜评估ECM重塑以及使用活细胞传感器定量评估TGFβ信号传导，TGFβ信号传导可增强胚胎型横纹肌肉瘤（FNRMS）中的细胞与ECM相互作用。我们还表明，配对盒基因3-叉头框蛋白O1（PAX3-FOXO1）增加一氧化氮合酶1（NOS1）的表达，刺激一氧化氮合成，从而抑制TGFβ信号传导并减少细胞与ECM的相互作用。我们认为，PAX3-FOXO1通过抑制细胞与ECM的相互作用来重新编程ECM锚定依赖性。融合基因可通过靶向破坏细胞与ECM的相互作用或TGFβ信号传导来确定对生长抑制的敏感性。该基因降低的锚定依赖性可能使细胞在循环中存活并增强FPRMS的转移潜能。