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

项目总结 尽管治疗方法有所进步，乳腺癌仍是癌症相关疾病的第二大诱因。 女性死亡人数。确定推动乳腺癌进展的关键信号通路是必要的 开发针对乳腺癌的新方法。成纤维细胞生长因子及其受体 (FGFR)在不同亚型的乳腺癌中都被激活，并与乳腺癌的进展有关 通过自分泌和旁分泌两种机制。这项提议重点是定义鉴别性小说 乳腺癌细胞中FGFR激活促进致瘤性改变的机制 在肿瘤微环境中，这有助于乳腺癌的进展。为此，我们集中力量 乳腺癌细胞中成纤维细胞生长因子/成纤维细胞生长因子受体信号的新转录靶点的鉴定 对基质环境的影响。使用FGFR驱动的乳腺肿瘤生长和进展模型， 我们已经产生了初步数据，将肿瘤细胞中成纤维细胞生长因子/纤维生长因子受体的激活与从头开始的胆固醇联系起来 综合和积累。此外，我们的发现表明，胆固醇在肿瘤细胞中积聚 促进免疫抑制的巨噬细胞群的产生。尽管成纤维细胞生长因子/FGFR轴 已被证明在某些生理环境中调节代谢功能，即成纤维细胞生长因子/成纤维细胞生长因子受体之间的联系 癌症中的胆固醇代谢还没有被研究过。本提案中所述的研究 将检验乳腺癌细胞中FGFR激活驱动肿瘤中胆固醇代谢的假设 这些变化导致了免疫抑制的微环境。建议进行的研究 特异性目标1乳腺癌细胞中成纤维细胞生长因子/成纤维细胞生长因子受体激活驱动胆固醇的机制 积累和储存。在特定目标2中的研究将检验FGFR驱动的胆固醇的影响 代谢对肿瘤微环境的影响。最后，《特定目标3》的研究将使用空间转录。 和多重成像技术以确定成纤维细胞生长因子/纤维细胞生长因子受体与人体胆固醇代谢之间的联系 乳腺癌。了解FGFR导致胆固醇改变的机制 肿瘤细胞中的新陈代谢及其对肿瘤微环境的影响将导致新的 针对肿瘤细胞和间质内恶性改变的治疗方法，导致 增强了治疗效果。

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.