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

癌细胞融合；

• 批准号: 10640109
• 负责人: Felicite K Noubissi
• 金额: $ 10.95万
• 依托单位: JACKSON STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10640109
• 关键词: Acceleration; Actins; Adhesions; Antineoplastic Agents; Apoptosis; Apoptotic; Automobile Driving; BAI1 gene; Bone Marrow; Breast; Breast Cancer Cell; Breast Cancer Treatment; Breast cancer metastasis; Cancer Model; Cancer Patient; Cause of Death; Cell Separation; Cell fusion; Cells; Communities; Development; Disease Progression; Disparity; Distant Metastasis; Drug resistance; Event; Exhibits; Forensic Medicine; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Polymorphism; Genomics; Goals; Health Disparities Research; Hematopoietic; Heterogeneity; Hypoxia; In Vitro; Incidence; Induction of Apoptosis; Invaded; 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; 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; black women; cancer cell; cancer health disparity; cancer heterogeneity; cancer prevention; 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; rac1 GTP-Binding Protein; receptor; single-cell RNA sequencing; statistics; stem; survival disparity; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor microenvironment

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.

项目摘要/摘要 大约90％的乳腺癌相关死亡是由局部侵袭和远处转移引起的 肿瘤细胞。在最近的白人妇女中，侵入性乳腺癌的发病率已稳定 十年来，黑人妇女的发病率每年稳定增加0.3％。 同时，随着时间的推移，两个人群的侵入性乳腺癌的存活率都升高。 但是，黑人妇女仍将她们降低10％。尽管这些差异的原因是多因素，但 分子机制和信号通路的差异可能 至少部分占生存差异。三重阴性乳腺癌在黑色中更常见 妇女显示出广泛的基因组异质性和对药物的抗性。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 白人和黑人妇女之间的乳腺癌异质性不成比例。不同的假设有 提出了转移的发展方式。但是，确切地提出了每种机制 远处尚未建立。研究表明，转移细胞是由融合引起的 原发性肿瘤细胞和造血谱系的细胞。包括我们在内的一些报告表明融合 可以快速多元化和随后的肿瘤内异质性支持转移。我们观察到 乳腺癌细胞融合发生在体内，并导致转移。我们还表明了融合 在非转移性乳腺癌细胞和间充质/多能茎/基质细胞（MSC）之间 通过涉及凋亡和磷脂酰丝氨酸依赖的机制增强了缺氧 （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 通过通过ELMO/DOCK180/RAC1途径发出信号。 ELMO/DOCK180/RAC1途径已激活 在乳腺癌中。因此，我们假设缺氧诱导的原发性肿瘤凋亡 通过涉及BAI1的机制刺激肿瘤细胞和肿瘤微环境细胞之间的融合 通过ELMO/DOCK180/RAC1途径激活和信号。我们的目标是调查 BAI1/Elmo/dock180/rac1途径在乳腺肿瘤细胞的融合机理中，从两种白色分离 和具有MSC的黑人妇女体外。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）中乳腺特异性BAI1基因敲除小鼠的能力634mul/j 发展乳腺癌转移的背景。这项研究的完成将有助于划定 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，可能是转移酶的机制。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/或预防转移性扩散。这 将有助于减少我们社区的乳腺癌差异。