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

  • Cell Signal. 2025 Oct:134:111904. doi: 10.1016/j.cellsig.2025.111904.
Panneerselvam Jayabal  1 ,  Xiuye Ma  1 ,  Yidong Chen  2 ,  Yaxia Yuan  3 ,  Yuzuru Shiio  4
Affiliations
  • 1. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
  • 2. 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.
  • 3. Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
  • 4. Greehey Children's Cancer Research Institute, 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; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA. Electronic address: [email protected].
PMID: 40451561 DOI: 10.1016/j.cellsig.2025.111904
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.

Keywords
C4orf48; Ewing sarcoma; FAT4; Hippo signaling; NELL2; NICOL; Secretome.
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