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

项目摘要 尽管在治疗选择方面取得了进展，但乳腺癌仍然是癌症相关疾病的第二大原因。 女性死亡。识别驱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在人类乳腺癌的亚型中被激活，并促进乳腺癌的进展 通过自分泌和旁分泌机制。这一建议的重点是界定识别小说 乳腺癌细胞中FGFR激活促进促肿瘤发生改变的机制 在肿瘤微环境中，这有助于乳腺癌的进展。为此，我们将重点放在 1）乳腺癌细胞中FGF/FGFR信号传导的新转录靶点，2）它们的 对基质环境的影响使用FGFR驱动的乳腺肿瘤生长和进展的模型， 我们已经产生了初步的数据，将肿瘤细胞中FGF/FGFR的激活与胆固醇的新生联系起来， 综合与积累。此外，我们的研究结果表明，肿瘤细胞中的胆固醇积累 促进免疫抑制性巨噬细胞群体的产生。虽然FGF/FGFR轴 在某些生理环境中，FGF/FGFR之间的联系已被证明可调节代谢功能， 胆固醇代谢在癌症中还没有研究。本提案中所述的研究 将检验乳腺癌细胞中FGFR的激活驱动肿瘤中胆固醇代谢的假设。 细胞，这些改变有助于免疫抑制微环境。拟议的研究 具体目标1将乳腺癌细胞中FGF/FGFR激活驱动胆固醇的机制 积累和储存。特定目标2的研究将检查FGFR驱动的胆固醇的影响 代谢对肿瘤微环境的影响最后，Specific Aim 3中的研究将使用空间转录组学 和多重成像技术，以确定FGF/FGFR和人体胆固醇代谢之间的联系 乳腺癌了解导致FGFR驱动的胆固醇改变的机制 肿瘤细胞中的代谢以及随后对肿瘤微环境的影响将导致新的肿瘤细胞的生长。 靶向肿瘤细胞和间质内的恶性改变的治疗方法， 增强治疗效果。

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.