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

肿瘤细胞簇诱导的信号传导在乳腺癌转移中的作用

基本信息

批准号：
9887195
负责人：
Kevin Jon Cheung
金额：
$ 40.26万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9887195
关键词：
Address Adhesions Affinity Aggressive behavior Apoptosis Area Automobile Driving Biological Assay Biological Markers Breast Breast Cancer Patient Breast cancer metastasis Cancer Patient Cell Culture Techniques Cell Proliferation Cells Cessation of life Clinical Communities Cooperative Behavior Data Data Set Diagnosis Disease Distant Environment Epidermal Growth Factor Receptor Event Feedback Fos-Related Antigens Frequencies Genetic Transcription Growth Hematopoietic Neoplasms Human In Situ In Vitro Individual Laboratories Lead Learning Life Ligands Ligation Light Lung Malignant Neoplasms Mammary Neoplasms Metastatic breast cancer Metastatic to Methods Micrometastasis Modeling Molecular Mus Neoplasm Circulating Cells Neoplasm Metastasis Organ Organoids Outcome Patient-Focused Outcomes Patients Plant Roots Play Positioning Attribute Privatization Proliferating Prostate Protein Tyrosine Kinase Receptor Activation Receptor Signaling Recurrence Research Resistance Resistance development Role Sampling Seeds Signal Transduction Site Survival Rate Testing Therapeutic Transcriptional Activation Woman Work activating transcription factor anticancer research base breast cancer survival burden of illness cancer recurrence cancer type early phase trial epidemiology study epigen human data improved in vivo innovation malignant breast neoplasm metastatic process mortality mouse model multidisciplinary neoplastic cell novel therapeutic intervention outcome forecast pre-clinical prevent programs success targeted treatment transcription factor tumor

项目摘要

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.

大多数乳腺癌死亡的根本原因是转移。研究界可以开发新的治疗方法来根除和预防转移性疾病。传统上，一种有希望的研究途径涉及肿瘤细胞的合作行为。转移被概念化为单个肿瘤细胞扩散到远处器官。 Cheung 研究小组和其他人的研究已经证实，肿瘤细胞簇会转移到在小鼠模型中，远距离器官比单细胞更有效，并且循环肿瘤细胞簇与人类不良的患者预后和治疗耐药性相关。负责最佳细胞簇的攻击以及消除细胞簇的治疗策略最近，张实验室发现了聚集的肿瘤细胞。细胞凋亡抗性、细胞增殖和分子表达变化的耗尽水平表明这些研究表明，酪氨酸激酶 EGFR 是细胞间相互合作的。在成簇肿瘤细胞中的细胞与细胞接触处被激活，他们确定 EGFR 和低亲和力 EGFR 配体 Epigen 对于簇依赖性增殖和转移定植是必需的。该项目将检验肿瘤细胞簇具有高度转移性的假设，因为它们包含一个私有的涉及 EGFR、Epigen 和转录因子 Fra-1 的信号传导环境，以及破坏此信号传导环境张实验室已经开发出信号环境将中和簇的转移潜力。技术创新的类器官和小鼠模型，用于研究基于簇的信号传导及其对使用这些模型，实验室将首先确定是否存在簇诱导的转移。效率具体取决于 Epigen 的局部激活其次，实验室将确定 Fra-1 的影响。肿瘤细胞簇特异性转移过程的转录程序和信号反馈回路，以及该计划是否取决于 Epigen 的存在。第三，实验室将对其进行补充。通过研究 EGFR、Epigen 与长期复发之间的关联得出的实验结果通过这种综合方法，张实验室将收集来自人类乳腺癌数据集的死亡率数据。了解肿瘤细胞倾向的合作分子机制正如提案中所描述的，这种理解很可能揭示分子。尽管这里提出的工作可以利用这些漏洞来开发新的抗转移疗法。重点是揭示针对乳腺癌肿瘤细胞簇的治疗策略，研究结果将可能与多种肿瘤类型相关。