Cancer cell fusion; A mechanism driving breast tumor heterogeneity and metastasis

癌细胞融合；

基本信息

批准号：
10402409
负责人：
Felicite K Noubissi
金额：
$ 18.75万
依托单位：
JACKSON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-08 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10402409
关键词：
Actins Adhesions Antineoplastic Agents Apoptosis Apoptotic Automobile Driving BAI1 gene Bone Marrow Breast Breast Cancer Cell Breast Cancer Treatment Breast cancer metastasis Cancer Patient Cause of Death Cell fusion Cells Communities Development Disease Progression Distant Metastasis Drug resistance Event Exhibits Forensic Medicine G-Protein-Coupled Receptors Genes Genetic Genetic Polymorphism Genomics Goals Health Disparities Research Hematopoietic Neoplasms Heterogeneity Hypoxia In Vitro Incidence Knock-out Knockout Mice Length Lesion Link Location Malignant Neoplasms Mammary Neoplasms Mesenchymal Metastatic Melanoma Modification Molecular Myoblasts Neoplasm Metastasis Nonmetastatic Pathway interactions Patients Pharmaceutical Preparations Population Prevention Primary Neoplasm Reporting Research Resistance Role Short Tandem Repeat Signal Pathway Signal Transduction Site Stress Stromal Cells Structure Survival Rate Time Transplantation United States Woman Xenograft procedure base black women cancer cell cancer health disparity cancer heterogeneity cancer statistics cancer therapy clinically relevant defined contribution drug development in vivo insight malignant breast neoplasm mesenchymal stromal cell mouse model neoplastic cell novel novel drug class novel therapeutics phosphatidylserine receptor prevent promoter receptor single-cell RNA sequencing stem survival disparity therapy development transcriptomics triple-negative invasive breast carcinoma tumor tumor heterogeneity tumor microenvironment

项目摘要

Project Summary/Abstract Approximately 90% of breast cancer-related deaths are caused by local invasion and distant metastasis of tumor cells. While invasive breast cancer incidence rates have been stabilized in white women in the recent decade, a steady increase in the incidence rates by 0.3% per year has been observed in black women. Meanwhile, the survival rates for invasive breast cancer have increased for both populations over time. However, they remain 10% lower for black women. Although the reasons for these disparities are multifactorial, differences in molecular mechanisms and signaling pathways driving the progression of the disease might account at least in part for the survival disparity. Triple negative breast cancer is more common in black women and was shown to exhibit extensive genomic heterogeneity and resistance to drug. In this study, we assess cancer cell fusion as a mechanism driving tumor heterogeneity and metastasis and a potential basis for the disproportion in breast cancer heterogeneity between white and black women. Different hypotheses have been put forward as to how metastasis develops. However, exactly how each of the mechanisms proposed so far is accomplished is yet to be established. Studies have suggested that metastatic cells result from the fusion of primary tumor cells and cells of hematopoietic lineage. Some reports including ours showed that fusion enables rapid diversification and subsequent intra-tumor heterogeneity supportive of metastasis. We observed that breast cancer cell fusion happens in vivo and contributes to metastasis. We also showed that fusion between non metastatic breast cancer cells and mesenchymal/multipotent stem/stromal cells (MSCs) was enhanced with hypoxia by a mechanism involving apoptosis and dependent of the phosphatidyl-serine (PtdSer) receptor BAI1. BAI1 and apoptotic cells were recently identified as new promoters of myoblast fusion by means of signaling through ELMO/Dock180/Rac1 pathway. The ELMO/Dock180/Rac1 pathway is activated in breast cancer. We therefore hypothesize that hypoxia stress-induced apoptosis in primary tumors stimulates fusion between tumor cells and cells of the tumor microenvironment by a mechanism involving BAI1 activation and signals through ELMO/Dock180/Rac1 pathway. Our objective is to investigate the role of BAI1/ELMO/Dock180/Rac1 pathway in the mechanism of fusion of breast tumor cells isolated from both white and black women with MSCs in vitro. We will also determine the function of BAI1 in breast cancer metastasis in vivo by analyzing the ability of breast specific Bai1 knockout mice in the FVB/N-Tg(MMTVPyVT)634Mul/J background to develop breast cancer metastasis. The completion of this study would contribute to delineating the mechanisms of cancer cell fusion, the role of cancer cell fusion in the development of molecular diversity in breast tumors, and potentially the mechanisms of metastases. This study might provide new strategies to developing a different class of drugs for breast cancer treatment and/or prevention of metastatic spread. This would contribute to the reduction in breast cancer disparities in our communities.

项目概要/摘要大约90%的乳腺癌相关死亡是由乳腺癌的局部侵袭和远处转移引起的肿瘤细胞。尽管近年来白人女性的浸润性乳腺癌发病率已经稳定十年来，黑人女性的发病率每年稳定增加 0.3%。与此同时，随着时间的推移，这两个人群的浸润性乳腺癌的生存率都有所增加。然而，黑人女性的比例仍然低 10%。尽管造成这些差异的原因是多方面的，驱动疾病进展的分子机制和信号通路的差异可能至少部分地解释了生存差异。三阴性乳腺癌在黑人中更常见女性，并被证明表现出广泛的基因组异质性和耐药性。在这项研究中，我们评估癌细胞融合作为驱动肿瘤异质性和转移的机制以及潜在的基础白人和黑人女性乳腺癌异质性不成比例。不同的假设有提出了转移如何发展的问题。然而，每种机制究竟是如何提出的已完成的工作还有待确定。研究表明，转移细胞是由融合产生的原发性肿瘤细胞和造血谱系细胞。包括我们在内的一些报告表明，融合实现快速多样化和随后支持转移的肿瘤内异质性。我们观察到乳腺癌细胞融合发生在体内并有助于转移。我们还表明融合非转移性乳腺癌细胞和间充质/多能干细胞/基质细胞（MSC）之间的比较通过涉及细胞凋亡和磷脂酰丝氨酸依赖性的机制在缺氧时增强 (PtdSer) 受体 BAI1。 BAI1和凋亡细胞最近被鉴定为成肌细胞融合的新启动子通过 ELMO/Dock180/Rac1 通路的信号传导。 ELMO/Dock180/Rac1 通路被激活在乳腺癌中。因此，我们假设缺氧应激诱导原发性肿瘤细胞凋亡通过涉及 BAI1 的机制刺激肿瘤细胞与肿瘤微环境细胞之间的融合通过 ELMO/Dock180/Rac1 途径激活和发出信号。我们的目标是调查 BAI1/ELMO/Dock180/Rac1通路在乳腺肿瘤细胞融合机制中的作用以及体外培养间充质干细胞的黑人女性。我们还将确定BAI1在乳腺癌转移中的功能通过分析 FVB/N-Tg(MMTVPyVT)634Mul/J 中乳腺特异性 Bai1 敲除小鼠的体内能力发展乳腺癌转移的背景。这项研究的完成将有助于描绘癌细胞融合的机制，癌细胞融合在分子多样性发展中的作用乳腺肿瘤，以及潜在的转移机制。这项研究可能会提供新的策略开发不同类别的药物用于乳腺癌治疗和/或预防转移扩散。这将有助于减少我们社区中乳腺癌的差异。