尤因肉瘤依赖于C4orf48/NICOL，一种由Hippo信号通路调控的NELL2辅因子。

Ewing sarcoma depends on C4orf48/NICOL, a NELL2 cofactor regulated by Hippo signaling.

作者信息

Jayabal Panneerselvam, Ma Xiuye, Chen Yidong, Yuan Yaxia, Shiio Yuzuru

机构信息

Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA.

Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Population Health Sciences, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA.

出版信息

Cell Signal. 2025 Oct;134:111904. doi: 10.1016/j.cellsig.2025.111904. Epub 2025 May 30.

DOI:10.1016/j.cellsig.2025.111904

PMID:40451561

Abstract

Ewing sarcoma is a cancer of bone and soft tissue in children characterized by a chromosomal translocation that fuses EWS and an ETS family transcription factor, most commonly FLI1. EWS-FLI1 is the driver of this cancer. Using secretome proteomics and molecular cell biology, we found that FAT4, an atypical cadherin activating Hippo signaling, is a transcriptional target of EWS-FLI and is a dependency in Ewing sarcoma. We determined that FAT4 - Hippo signaling regulates the expression of a secreted polypeptide, C4orf48/NICOL. We demonstrate that Ewing sarcoma depends on C4orf48, which functions as a cofactor for NELL2, a cytokine we previously identified as a critical dependency in Ewing sarcoma. These results reveal C4orf48 as a targetable dependency that links FAT4 - Hippo signaling and NELL2 signaling in Ewing sarcoma.

摘要

尤因肉瘤是一种发生于儿童骨骼和软组织的癌症，其特征是一种染色体易位，该易位使EWS与ETS家族转录因子（最常见的是FLI1）融合。EWS-FLI1是这种癌症的驱动因素。通过分泌蛋白质组学和分子细胞生物学方法，我们发现FAT4（一种激活Hippo信号的非典型钙黏蛋白）是EWS-FLI的转录靶点，并且是尤因肉瘤生长所必需的。我们确定FAT4-Hippo信号调节一种分泌多肽C4orf48/NICOL的表达。我们证明尤因肉瘤依赖于C4orf48，C4orf48作为NELL2的辅助因子发挥作用，NELL2是我们之前确定的尤因肉瘤生长所必需的一种细胞因子。这些结果揭示了C4orf48是一个可靶向的生长必需因子，它在尤因肉瘤中连接了FAT4-Hippo信号和NELL2信号。