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Transcriptomic profiling of E0771 breast tumors grown in wild-type versus uPAR-deficient hosts

ABSTRACT: The goal of this study is to define the contribution of host-derived urokinase plasminogen activator receptor (uPAR) to the tumor microenvironment in breast cancer. While uPAR is well recognized for its tumor-intrinsic roles, its functions within the host compartment, particularly in shaping immune and stromal responses, remain poorly understood. Using the syngeneic E0771 murine breast cancer model, we compared transcriptomic profiles of primary tumors grown in wild-type versus uPAR-deficient hosts to identify gene expression programs associated with loss of host uPAR. Bulk RNA sequencing was employed to capture global changes in tumor-associated transcriptional networks, with particular emphasis on immune-related pathways, antigen presentation, extracellular matrix remodeling, and tumor–host crosstalk. The objective of this work is to establish host-derived uPAR as a regulator of the tumor microenvironment and to provide a transcriptomic framework linking uPAR deficiency to altered immune contexture and microenvironmental signaling. This dataset is intended to support mechanistic interpretation of tumor–host interactions and to serve as a resource for future studies investigating uPAR-targeted strategies in breast cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE315798 | GEO | 2026/04/23

REPOSITORIES: GEO

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Project description:Chimeric Antigen Receptor (CAR) T cells have demonstrated transformative efficacy in hematologic malignancies and have shown promise in non-cancer contexts such as autoimmune diseases. We previously identified the urokinase plasminogen activator receptor (uPAR) as a cell-surface protein expressed on subsets of myeloid cells and broadly upregulated in senescent states. Murine uPAR-targeting CAR T cells can ameliorate fibrosis and prophylactically prevent metabolic syndrome in aged mice, paving the way for their use in senescence-driven pathologies. uPAR can also be expressed at high levels in cancer and, by performing a pan-cancer analysis, we now show that subsets of most tumor types display strong uPAR expression, which correlates with an epithelial-mesenchymal transition (EMT)-like state, increased fibrosis, metastasis, and poor patient outcomes. Single-cell and spatial analyses revealed that tumors with high uPAR expression in tumor cells often harbor senescent-like, uPAR-positive stromal cells, typically subsets of fibroblasts and macrophages. In mouse models, CAR T cells with uPAR-targeting single-chain variable fragments (scFvs) showed potent and persistent efficacy against multiple tumor types. In the context of high-grade serous ovarian cancer, adjuvant CAR T cell treatment following primary tumor debulking surgery cured mice by eliminating distal organ metastases. uPAR CAR T cells were well-tolerated, demonstrating efficacy in syngeneic and humanized immune system models without significant disruption of the myeloid compartment. Beyond direct tumor targeting, uPAR facilitated non-invasive cancer monitoring via soluble uPAR and PET imaging. Senescence-inducing therapies further enhanced uPAR expression and showed combinatorial activity with uPAR CAR T cells. These findings establish uPAR CAR T cells as a cancer-agnostic therapeutic strategy with a favorable safety profile and clear clinical potential in oncology, including solid tumors harboring a fibrotic tumor microenvironment linked to accumulation of senescent stromal cells.

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Transcriptomic profiling of E0771 breast tumors grown in wild-type versus uPAR-deficient hosts

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