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

FGFR 介导的肿瘤间质相互作用对乳腺癌生长和进展的贡献

• 批准号: 10445564
• 负责人: Kathryn L Schwertfeger
• 金额: $ 37.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445564
• 关键词: Automobile Driving; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Cancer Etiology; Cell Culture Techniques; Cessation of life; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Coculture Techniques; Data; Development; Disease; Environment; Esterification; Exhibits; FGFR1 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Generations; Genetic; Genetic Transcription; Goals; Growth; Health; Human; Imaging Techniques; Lead; Ligands; Link; Lipids; Liver; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Modeling; Mus; Neoplasm Metastasis; Pathway interactions; Patient-Focused Outcomes; Physiological; Population; Receptor Activation; Receptor Signaling; Regulation; Relapse; Research; Resistance; SRE-2 binding protein; Sampling; Signal Pathway; Site; Sterol O-Acyltransferase; Stromal Cells; Stromal Neoplasm; Testing; Therapeutic; Tissues; Treatment Efficacy; Woman; aggressive breast cancer; autocrine; base; bone; breast cancer progression; cancer cell; cell stroma; clinically relevant; experimental study; immunosuppressive macrophages; improved; inhibitor; lipid metabolism; macrophage; malignant breast neoplasm; mouse model; multiplexed imaging; neoplastic cell; novel; novel strategies; novel therapeutic intervention; paracrine; patient subsets; prevent; promoter; receptor; response; targeted treatment; transcriptomics; translational impact; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic

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.

项目概要 尽管治疗方案取得了进步，乳腺癌仍然是癌症相关疾病的第二大原因。 女性死亡。确定驱动乳腺癌进展的关键信号通路对于 开发针对乳腺癌的新方法。成纤维细胞生长因子 (FGF) 及其受体 (FGFR) 在不同亚型的人类乳腺癌中被激活，并促进乳腺癌进展 通过自分泌和旁分泌机制。该提案的重点是定义识别新颖性 乳腺癌细胞中 FGFR 激活导致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，我们重点 确定 1) 乳腺癌细胞中 FGF/FGFR 信号传导的新转录靶标，以及 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模型， 我们已经生成了初步数据，将肿瘤细胞中的 FGF/FGFR 激活与从头胆固醇联系起来 合成和积累。此外，我们的研究结果表明，肿瘤细胞中胆固醇的积累 促进免疫抑制巨噬细胞群的产生。虽然 FGF/FGFR 轴 已被证明可以在某些生理环境中调节代谢功能，FGF/FGFR 之间的联系 尚未在癌症中研究胆固醇代谢。本提案中描述的研究 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，这些改变有助于形成免疫抑制的微环境。提出的研究 具体目标 1 将探讨乳腺癌细胞中 FGF/FGFR 激活驱动胆固醇的机制 积累和储存。具体目标 2 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，Specific Aim 3 中的研究将使用空间转录组学 和多重成像技术来确定 FGF/FGFR 与人体胆固醇代谢之间的联系 乳腺癌。了解 FGFR 驱动的胆固醇改变的机制 肿瘤细胞的代谢以及随后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 增强治疗功效。