Role of tumor cell cluster-induced signaling in breast cancer metastasis

大多数乳腺癌死亡的根本原因是转移。通过剖析驱动它的分子事件， 研究界可以开发新的治疗方法来根除和预防转移性疾病。 一个有希望的研究途径涉及到肿瘤细胞的合作行为。按照惯例， 转移是指单个肿瘤细胞向远处器官扩散。然而，最近 Cheung研究小组和其他人的研究已经证实，肿瘤细胞簇转移到 在小鼠模型中，远距离器官比单个细胞更有效，循环中的肿瘤细胞群 与不良的患者结局和人类的治疗阻力有关。分子机制 负责肿瘤细胞簇的侵袭和消除肿瘤细胞簇的最佳治疗策略 仍然是默默无闻的。最近，Cheung实验室发现，聚集的肿瘤细胞显示 高水平的抗凋亡、细胞增殖和分子表达的变化 细胞之间相互协作。这些研究表明，酪氨酸激酶EGFR是 在聚集的肿瘤细胞中的细胞-细胞接触处被激活，它们建立了EGFR和低亲和力的EGFR 表位配基是簇状依赖的增殖和转移定植所必需的。建议数 Project将测试这一假设，即肿瘤细胞团是高度转移的，因为它们包含一种 涉及EGFR、epigen和转录因子Fra-1的信号环境，并破坏这一过程 信号环境将中和集群的转移潜力。张实验室已经开发出 技术创新的有机物和小鼠模型来研究基于集群的信号及其对 体内转移。使用这些模型，实验室将首先确定集群诱导的转移 效率特别依赖于表观色素的局部激活。其次，实验室将确定Fra-1的影响 肿瘤细胞群特有的转移过程的转录程序和信号反馈环， 以及这一计划是否取决于埃皮根的存在。第三，实验室将补充其 通过研究表皮生长因子受体、表皮生长因子与长期复发和 来自人类乳腺癌数据集的死亡率数据。通过这种综合的方法，张国荣实验室将 发展对肿瘤细胞倾向的合作分子机制的理解 簇状转移。正如提案中所描述的，这种理解很可能揭示分子 可以被利用来开发新的抗转移疗法的漏洞。尽管这里提出的工作 专注于揭示针对乳腺癌肿瘤细胞团的治疗策略，研究结果将 可能与多种肿瘤类型有关。

The root cause of most breast cancer deaths is metastasis. By dissecting the molecular events driving it, the research community can develop new therapeutic approaches to eradicate and prevent metastatic disease. One promising avenue of research involves the cooperative behavior of tumor cells. Conventionally, metastasis is conceptualized as the dissemination of individual tumor cells to distant organs. However, recent studies by the Cheung research group and others have established that clusters of tumor cells metastasize to distant organs more efficiently than single cells in mouse models, and that circulating tumor cell clusters are associated with poor patient outcomes and therapy resistance in humans. The molecular mechanisms responsible for aggression in tumor cell clusters and the optimal therapeutic strategies to eliminate clusters have remained obscure. Recently, the Cheung laboratory has found that clustered tumor cells display heightened levels of apoptosis resistance, cell proliferation, and changes in molecular expression that indicate that the cells are cooperating with one another. These studies reveal that the tyrosine kinase EGFR is activated at cell-cell contacts in clustered tumor cells, and they establish that EGFR and the low-affinity EGFR ligand Epigen are necessary for cluster-dependent proliferation and metastatic colonization. The proposed project will test the hypothesis that tumor cell clusters are highly metastatic because they contain a private signaling environment involving EGFR, Epigen, and the transcription factor Fra-1, and that disrupting this signaling environment will neutralize clusters’ metastatic potential. The Cheung lab has already developed technically innovative organoid and murine models to study cluster-based signaling and its impact on metastasis in vivo. Using these models, the lab will first determine whether cluster-induced metastatic efficiency depends specifically on local activation by Epigen. Second, the lab will determine the impact of Fra-1 transcriptional programs and signaling feedback loops on metastatic processes specific to tumor cell clusters, as well as whether this program depends on the presence of Epigen. Third, the lab will supplement its experimental findings by studying the association between EGFR, Epigen, and long-term recurrence and mortality data from human breast cancer datasets. Through this integrated approach, the Cheung lab will develop an understanding of the cooperative molecular mechanisms that underlie the propensity of tumor cell clusters to metastasize. As described in the proposal, this understanding is likely to reveal molecular vulnerabilities that can be exploited to develop new anti-metastatic therapies. Although the work proposed here focuses on uncovering therapeutic strategies to target tumor cell clusters in breast cancer, the findings will potentially be relevant to a wide range of tumor types.