Hypertrophic adipocytes as biophysical mediators of breast cancer progression

肥大脂肪细胞作为乳腺癌进展的生物物理介质

• 批准号: 10751284
• 负责人: Garrett F Beeghly
• 金额: $ 4.66万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2025-08-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751284
• 关键词: Actins; Address; Adipocytes; Adipose tissue; Adopted; Adult; Biogenesis; Biological Assay; Biological Markers; Biophysics; Biopsy; Body mass index; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer cell line; Cancer Prognosis; Cell Proliferation; Cell Separation; Cells; Chemoresistance; Clinic; Clinical; Coculture Techniques; Communication; Cues; Cytoskeleton; Data; Data Analyses; Diameter; Exhibits; Experimental Designs; Frequencies; Genes; Goals; Hypertrophy; In Vitro; Incidence; Inguinal lymph node group; Injections; Institution; Intervention; Invaded; Lipids; Malignant Neoplasms; Mammaplasty; Mammary Duct; Mass Spectrum Analysis; Mediating; Mediator; Mentors; Mentorship; Metabolic Diseases; Metabolic dysfunction; Methods; MicroRNAs; Microfluidics; Molecular; Mus; Obese Mice; Obesity; Obesity Epidemic; Organ; Organoids; Patient-Focused Outcomes; Patients; Phenotype; Prognosis; Prognostic Marker; Proliferating; Research; Research Personnel; Risk Factors; Science; Smoking; Sorting; Techniques; Thinness; Tissues; Training; Transcriptional Regulation; Tumor Promotion; United States; Vesicle; Weight; Weight Gain; Woman; Work; behavior in vitro; breast cancer progression; cell behavior; cell motility; cell type; cohort; experimental study; extracellular vesicles; fatty acid oxidation; genetic inhibitor; humane endpoint; imaging study; implantation; improved; in vivo; interest; malignant breast neoplasm; mammary; migration; mortality; nanoparticle; neoplastic cell; obese person; pharmacologic; precursor cell; skills; targeted treatment; transcriptome sequencing; tumor; tumor metabolism; tumor progression; vesicular release

PROJECT SUMMARY Over 40% of adult women in the U.S. are obese and obesity will soon overtake smoking as the leading risk factor for cancer. For breast cancer, obese women demonstrate both a higher incidence and higher rate of cancer- related mortality compared to normal weight women. While many studies focus on potential systemic connections behind this observation, the breast is rich in white adipose tissue (WAT), which is highly remodeled in the context of obesity, and thus local tissue-resident cues must also be considered. At the cellular level, white adipocytes are the functional units of WAT and secrete extracellular vesicles (EVs) that promote tumor progression. Recent studies indicate that adipocyte-derived EVs contain lipids and other metabolites for fatty acid oxidation that modulate tumor cell metabolism to increase migration, proliferation, and chemoresistance. In obese individuals, adipocytes become hypertrophic with known consequences for metabolic disease. Whether adipocyte hypertrophy similarly impacts breast cancer risk and prognosis is less clear. Preliminary data in this proposal indicate that hypertrophic adipocytes promote the proliferation and migration of co-cultured tumor cells to a greater extent than donor-matched, non-hypertrophic control adipocytes. Moreover, I found that hypertrophic adipocytes secrete more EVs and exhibit remodeled cortical actin. Given that the actin cytoskeleton mediates the biogenesis of EVs by other cell types, this proposal aims to investigate if hypertrophy, remodeled cortical actin, and increased EV secretion are interconnected. Moreover, the proposed research also aims to discern if these differences impact breast cancer progression by altering tumor cell metabolism. In Specific Aim 1, I will characterize the concentration, size distribution, and cargo of EVs released by hypertrophic vs. control adipocytes via nanoparticle tracking analysis and mass spectrometry. In Specific Aim 2, I will expose breast cancer cells to EVs secreted by hypertrophic vs. control adipocytes to assess how treatment impacts tumor cell behavior in vitro and in vivo. Moreover, I will perform pharmacological and genetic inhibitor studies to determine if altered fatty acid oxidation underpins any observed differences in tumor cell phenotypes. Collectively, this work will help discern if hypertrophic adipocytes constitute a distinct subpopulation of cells conducive to tumor progression and thus contribute to the poor prognosis of obesity-associated breast cancer. In the clinic, identified molecular mechanisms between adipocytes and tumor cells could be targeted therapeutically and the degree of mammary adipocyte hypertrophy could serve as a prognostic biomarker for patient outcomes. Beyond research, I will develop skills around experimental design, data analysis, mentorship, and science communication through my training goals and team of mentors outlined in this proposal. These skills will be essential to achieve my long- term professional goal of becoming an independent investigator at a research-focused institution.

项目总结 美国超过40%的成年女性肥胖，肥胖将很快取代吸烟成为主要的危险因素 治疗癌症。对于乳腺癌，肥胖女性表现出更高的发病率和更高的癌症发病率- 与正常体重妇女的相关死亡率进行比较。虽然许多研究都集中在潜在的系统性 在这一观察背后的联系，乳房富含白色脂肪组织(WAT)，这是高度重塑的 在肥胖的背景下，因此也必须考虑局部组织驻留的线索。在细胞水平上，白色 脂肪细胞是WAT的功能单位，分泌细胞外小泡(EV)促进肿瘤生长 进步。最近的研究表明，脂肪细胞来源的EV含有脂肪和其他脂肪代谢产物。 调节肿瘤细胞新陈代谢以增加迁移、增殖和抗药性的酸氧化。在……里面 肥胖的人，脂肪细胞变得肥大，导致已知的代谢性疾病。是否 脂肪细胞肥大同样会影响乳腺癌的风险和预后。本报告中的初步数据 提示肥大脂肪细胞促进共培养肿瘤细胞的增殖和迁移 比供者匹配的非肥大对照脂肪细胞更大程度上。此外，我发现肥大 脂肪细胞分泌更多的EV，并显示重塑的皮质肌动蛋白。鉴于肌动蛋白细胞骨架在 通过其他细胞类型的EVS的生物发生，这一建议旨在调查是否肥大，重塑的皮质 肌动蛋白和EV分泌增加是相互关联的。此外，这项拟议的研究还旨在辨别 这些差异通过改变肿瘤细胞代谢来影响乳腺癌的进展。在具体目标1中，我将 描述肥厚性与非肥厚性EVS的浓度、大小分布和载量 通过纳米颗粒跟踪分析和质谱学分析脂肪细胞。在《特定目标2》中，我会露出乳房 肥大与对照脂肪细胞分泌的EVS对癌细胞的影响评估治疗对肿瘤细胞的影响 在体外和体内的行为。此外，我将进行药理和遗传抑制物研究，以确定 如果脂肪酸氧化改变是任何观察到的肿瘤细胞表型差异的基础。总体而言，这项工作 将有助于辨别肥大的脂肪细胞是否构成了有利于肿瘤的不同细胞亚群 并因此导致肥胖相关乳腺癌的不良预后。在诊所里，确认了 脂肪细胞和肿瘤细胞之间的分子机制可以被靶向治疗，并且程度 乳腺脂肪细胞肥大可作为判断患者预后的生物标志物。除了研究之外， 我将通过以下途径培养实验设计、数据分析、指导和科学交流的技能 我的培训目标和导师团队在此提案中概述。这些技能将是实现我的长期- 成为一家专注于研究的机构的独立调查员的术语专业目标。