Autocrine TGFβ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma.

ABSTRACT: Subpopulations of cancer-associated fibroblast (CAF)-like tumor cells deposit extracellular matrix (ECM) proteins that support Ewing sarcoma (EwS) progression and metastasis. We previously showed a hallmark of CAF-like EwS cells is their hybrid transcriptional state wherein the driver fusion oncogene, EWS::FLI1, maintains activation of proliferative programs but loses capacity to repress mesenchymal genes. Here, we studied primary patient tumors and cell line models to identify molecular drivers of this hybrid state. Our data reveal that hybrid EwS cells are induced and maintained by a transforming growth factor-β (TGFβ) signaling positive feedback loop. Hybrid cells derepress TGFBR2 and up-regulate expression and secretion of TGFβ2 to sustain pathway activation and ECM deposition.

SUBMITTER: Wrenn ED 

PROVIDER: S-EPMC12822632 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature