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TGFβ inhibition during radiation therapy enhances immune cell infiltration and decreases metastases in a novel humanized mouse model Ewing sarcoma.

ABSTRACT: Ewing sarcoma is an aggressive cancer most commonly diagnosed in adolescents and young adults. Various mechanisms of TGFβ inhibition are being tested in clinical trials for patients with relapsed Ewing sarcoma. However, the functional impact of TGFβ inhibition on the Ewing tumor microenvironment remains largely unstudied given the historical lack of immunocompetent preclinical models of Ewing sarcoma. Here, we use single cell RNAseq analysis of human Ewing tumors to demonstrate that immune cells are the largest source of TGFβ production in the human Ewing tumor microenvironment. We develop and utilize a humanized mouse model of Ewing sarcoma to study the effect of TGFβ inhibition on the Ewing tumor immune microenvironment both at baseline and during radiation therapy, a treatment that enhances TGFβ activation and is often used to treat patients with aggressive Ewing sarcoma. Finally, we utilize a bivalent ligand TGFβ TRAP and demonstrate that, in combination with radiation, TGFβ inhibition both increases immune cell infiltration in Ewing tumors and decreases lung metastatic burden.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261693 | GEO | 2025/05/20

REPOSITORIES: GEO

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Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.

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TGFβ inhibition during radiation therapy enhances immune cell infiltration and decreases metastases in a novel humanized mouse model Ewing sarcoma.

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