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

项目摘要/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。虽然白人女性的浸润性乳腺癌发病率在最近几年已经稳定下来 十年来，黑人妇女的发病率以每年0.3%的速度稳步增长。 与此同时，随着时间的推移，两个人群的浸润性乳腺癌的存活率都有所上升。 然而，黑人女性的这一比例仍然低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 至少在一定程度上解释了生存差距的原因。三阴性乳腺癌在黑人中更为常见 并显示出广泛的基因组异质性和对药物的抗药性。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的不比例。不同的假设有 关于肿瘤转移是如何发展的已经提出了。然而，每一种机制到底是如何提出的 远距离的成就还有待确立。研究表明，转移细胞是融合的结果。 原发肿瘤细胞和造血系细胞。包括我们在内的一些报告显示，核聚变 能够实现快速多样化和随后的肿瘤内异质性，支持转移。我们观察到 乳腺癌细胞融合在体内发生，并有助于转移。我们还展示了核聚变 非转移性乳腺癌细胞与间充质/多能干细胞/基质细胞(MSCs)之间的相互作用 通过细胞凋亡和磷脂酰丝氨酸依赖机制增强低氧 (PtdSer)受体BAI1。BAI1和凋亡细胞是新近发现的成肌细胞融合的新启动子 通过Elmo/Dock180/rac1通路传递信号。Elmo/Dock180/rac1通路被激活 在乳腺癌方面。因此，我们假设低氧应激诱导原发肿瘤细胞凋亡 通过BAI1参与的机制促进肿瘤细胞与肿瘤微环境细胞的融合 通过Elmo/Dock180/rac1途径激活和传递信号。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 以及在体外拥有间充质干细胞的黑人女性。我们还将确定BAI1在乳腺癌转移中的作用 FVB/N-TG(MMTVPyVT)634Mul/J小鼠体内BAI1基因敲除能力分析 研究背景乳腺癌发生转移。这项研究的完成将有助于划定 肿瘤细胞融合的机制，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来 开发用于乳腺癌治疗和/或防止转移扩散的不同类别的药物。这 将有助于减少我们社区中乳腺癌的差距。

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.