Contributions of FGFR-Mediated Tumor-Stromal Interactions to Breast Cancer Growth and Progression

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PROJECT SUMMARY Despite advances in treatment options, breast cancer remains the second leading cause of cancer-related deaths in women. Identifying key signaling pathways that drive breast cancer progression is necessary for developing new approaches to target breast cancer. Fibroblast growth factors (FGFs) and their receptors (FGFR) are activated in human breast cancers across subtypes and contribute to breast cancer progression via both autocrine and paracrine mechanisms. The focus of this proposal is to define identify novel mechanisms through which FGFR activation in breast cancer cells contributes to pro-tumorigenic alterations in the tumor microenvironment, which contribute to breast cancer progression. To this end, we have focused on identifying 1) novel transcriptional targets of FGF/FGFR signaling in breast cancer cells and 2) their impact on the stromal environment. Using a model of FGFR-driven mammary tumor growth and progression, we have generate preliminary data that link FGF/FGFR activation in tumor cells with de novo cholesterol synthesis and accumulation. Furthermore, our findings suggest that cholesterol accumulation in tumor cells promotes the generation of an immunosuppressive macrophage population. Although the FGF/FGFR axis has been shown to regulate metabolic functions in some physiological contexts, the link between FGF/FGFR and cholesterol metabolism has not been investigated in the cancer. The studies described in this proposal will test the hypothesis that activation of FGFR in breast cancer cells drives cholesterol metabolism in tumor cells and that these alterations contribute to an immunosuppressive microenvironment. Studies proposed in Specific Aim 1 will the mechanisms by which FGF/FGFR activation in breast cancer cells drives cholesterol accumulation and storage. Studies in Specific Aim 2 will examine the impact of FGFR-driven cholesterol metabolism on the tumor microenvironment. Finally, studies in Specific Aim 3 will use spatial transcriptomics and multiplex imaging techniques to identify links between FGF/FGFR and cholesterol metabolism in human breast cancers. Understanding the mechanisms that contribute to FGFR-driven alterations in cholesterol metabolism in tumor cells and subsequent impacts on the tumor microenvironment will lead to novel therapeutic approaches that target malignant alterations within both the tumor cell and the stroma, leading to enhanced therapeutic efficacy.