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.

项目摘要 美国以上40％的成年妇女肥胖，肥胖很快将超过吸烟作为领先的危险因素 用于癌症。对于乳腺癌，肥胖女性既表现出更高的发病率和更高的癌症率 与正常体重女性相比，相关死亡率。许多研究重点是潜在的系统性 该观察结果背后的连接，乳房富含白色脂肪组织（WAT），该乳房重塑了 在肥胖症的背景下，还必须考虑局部居民提示。在细胞水平，白色 脂肪细胞是WAT和分泌细胞外囊泡（EV）的功能单位，可促进肿瘤 进展。最近的研究表明，脂肪细胞衍生的电动汽车含有脂质和其他代谢物用于脂肪 调节肿瘤细胞代谢以增加迁移，增殖和化学抗性的酸氧化。在 肥胖的个体，脂肪细胞变成肥厚的，对代谢疾病的已知后果。无论 脂肪细胞肥大类似地影响乳腺癌的风险和预后不明显。初步数据 提案表明肥厚脂肪细胞促进共培养肿瘤细胞的增殖和迁移 比供体匹配的非肌营养性对照脂肪细胞更大程度地。而且，我发现肥厚 脂肪细胞分泌更多的电动汽车，并展示重塑的皮质肌动蛋白。鉴于肌动蛋白细胞骨架介导 其他细胞类型的电动汽车生物发生，该建议旨在研究肥大，重塑皮质 肌动蛋白和EV分泌增加是相互联系的。此外，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。在特定的目标1中，我会 表征由肥厚型与控制释放的电动汽车的浓度，尺寸分布和货物 通过纳米颗粒跟踪分析和质谱法的脂肪细胞。在特定的目标2中，我将暴露乳房 由肥厚性与对照脂肪细胞分泌的癌细胞，以评估治疗如何影响肿瘤细胞 体外和体内行为。此外，我将进行药理学和遗传抑制剂研究以确定 如果改变的脂肪酸氧化为肿瘤细胞表型的任何观察到的差异。总的来说，这项工作 将有助于辨别肥厚的脂肪细胞是否构成了有利于肿瘤的细胞的独特亚群 进展，从而导致肥胖相关乳腺癌的预后不良。在诊所中，确定 脂肪细胞和肿瘤细胞之间的分子机制可以治疗靶向 乳腺脂肪细胞肥大可以作为患者预后的预后生物标志物。超越研究， 我将通过实验设计，数据分析，指导和科学沟通来发展技能 我的培训目标和导师团队在此提案中概述了。这些技能对于实现我的长期至关重要 成为以研究为重点机构的独立研究者的任期专业目标。