Evaluating the impact of obesity-associated inflammation on breast cancer heterogeneity and metastasis using single-cell RNA-seq

使用单细胞 RNA-seq 评估肥胖相关炎症对乳腺癌异质性和转移的影响

基本信息

项目摘要

Project Abstract Breast cancer remains the second-leading cause of cancer-related death in the US. Obesity is an established risk factor for several aggressive breast cancer subtypes, and is also associated with increased breast cancer metastasis and mortality. On a cellular level, obesity drives increased inflammation and dysregulated leptin signaling, both of which have been independently shown to increase cancer cell migration and invasion. However, the exact mechanisms by which these drivers link obesity to increased breast cancer metastasis are poorly understood. Since the prevalence of obesity in the US and many other countries is very high, and the vast majority of breast cancer-related deaths are due to metastatic disease, intervention strategies for breaking the link between obesity and breast cancer metastasis are urgently needed to reduce breast cancer mortality. Several series of metastatic breast cancer cell lines (each series driven by a different genetic alteration and varying in metastatic potential) have been developed that can be used in orthotopic transplant models to study the effects of obesity on metastatic breast cancer. Our preliminary findings in one of these models support the obesity-metastasis link and suggest obesity-induced inflammation may underlie this link. This proposal will use murine models of obesity and metastatic mammary cancer in concert with several state-of-the-art mechanistic approaches, including multiplexed assays of inflammatory markers and a high-throughput single-cell RNA sequencing approach for assessing the tumor microenvironment, to rigorously test the hypothesis that obesity- associated inflammation and leptin signaling act together to enhance breast cancer metastasis by driving a cancer stem-cell phenotype. This hypothesis will be tested with two integrated specific aims: Aim 1. Quantify the impact of obesity and anti-inflammatory treatment on tumor growth, metastasis, metabolic phenotype, and inflammatory and stem-like markers in three separate metastatic murine mammary tumor lines. Aim 2. Define the impact of obesity and anti-inflammatory treatment on mammary tumor gene expression and metastatic potential using a high-throughput, unbiased single-cell RNA-sequencing approach. Using this data, potential drivers in one metastatic cell line will be identified, manipulated using CRISPR, confirmed in vitro and validated in the other two cell lines. Following validation, the altered cell line will be assayed in vivo to test the metastatic potential manipulated line in a pilot mouse study comparing lean and obese animals. This proposal aims to define molecular characteristics enriched in breast cancer metastasis and ultimately to identify therapeutic targets to help decrease breast cancer mortality by limiting metastasis, particularly in the obese patient population. Combined with the exceptional training environment at UNC, comprehensive mentoring from Drs. Hursting and Anders, and a focused training plan, this fellowship will provide a critical foundation for developing my future career as an independently-funded physician-scientist in the field of cancer metastasis.
项目摘要 乳腺癌仍然是美国癌症相关死亡的第二大原因。肥胖是一种既定的 几种侵袭性乳腺癌亚型的危险因素,也与乳腺癌的增加有关 转移和死亡率。在细胞水平上,肥胖导致炎症增加和瘦素失调 信号,这两种信号都被独立地证明可以增加癌细胞的迁移和侵袭。 然而,这些驱动因素将肥胖与乳腺癌转移增加联系在一起的确切机制是 人们对此知之甚少。由于肥胖症在美国和许多其他国家的流行率非常高,而且 大多数乳腺癌相关死亡是由于转移性疾病,干预策略打破了 肥胖与乳腺癌转移之间的联系是降低乳腺癌死亡率的迫切需要。 几系列转移性乳腺癌细胞系(每一系列由不同的基因改变和 不同的转移潜能)已经被开发,可用于原位移植模型来研究 肥胖对转移性乳腺癌的影响。我们在其中一个模型中的初步发现支持 肥胖-转移联系,并提示肥胖诱导的炎症可能是这一联系的基础。这项提案将使用 肥胖和转移性乳腺癌小鼠模型与几种最新机制的结合 方法,包括炎性标志物的多重分析和高通量单细胞RNA 用于评估肿瘤微环境的排序方法,以严格检验肥胖- 相关的炎症和瘦素信号共同作用,通过驱动 肿瘤干细胞表型。这一假设将通过两个综合的具体目标进行检验: 目的1.量化肥胖和抗炎治疗对肿瘤生长、转移、代谢的影响 三种不同的转移性小鼠乳腺肿瘤株的表型、炎性和干细胞性标志物。 目的2.明确肥胖和抗炎治疗对乳腺肿瘤基因表达和抗炎治疗的影响 利用高通量、无偏倚的单细胞RNA测序方法研究转移潜能。使用这些数据, 一个转移细胞系中的潜在驱动因素将被识别,使用CRISPR进行操纵,在体外得到确认,并 在另外两个细胞系中进行了验证。在验证之后,改变的细胞系将在体内进行测试,以测试 在一项比较瘦小动物和肥胖动物的先导性小鼠研究中,转移潜能被操纵线。这项建议 目的是确定乳腺癌转移中丰富的分子特征,并最终确定 通过限制转移来帮助降低乳腺癌死亡率的治疗目标,特别是在肥胖者 病人群体。与北卡罗来纳大学卓越的培训环境相结合,来自 赫斯汀博士和安德斯博士,以及一个有重点的培训计划,这一奖学金将为 发展我未来的职业生涯,成为一名独立资助的癌症转移领域的内科科学家。

项目成果

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