Project Details
Description
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.
Status | Active |
---|---|
Effective start/end date | 4/1/17 → 6/30/24 |
Funding
- National Cancer Institute: $352,275.00
- National Cancer Institute: $352,275.00
- National Cancer Institute: $351,704.00
- National Cancer Institute: $349,416.00
- National Cancer Institute: $378,466.00
- National Cancer Institute: $341,706.00
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