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。通过解剖驱动它的分子事件，研究界可以开发新的治疗方法来放射素并预防转移性疾病。一项承诺的研究途径涉及肿瘤细胞的合作行为。常规上转移被概念化为单个肿瘤细胞向远处器官的传播。但是，最近张研究小组和其他人的研究确定，肿瘤细胞的聚类转移到在小鼠模型中，远处器官比单个细胞更有效，并且循环肿瘤细胞簇是与人类患者结局不良和抗治疗性相关。分子机制负责在肿瘤细胞簇中积极进取和消除簇的最佳治疗策略保持晦涩难懂。最近，张实验室发现簇状肿瘤细胞显示凋亡耐药性，细胞增殖和分子表达的变化升高，这表明细胞彼此合作。这些研究表明酪氨酸激酶EGFR是在聚类的肿瘤细胞中激活在细胞细胞接触处，它们确定了EGFR和低亲和力EGFR 配体表皮性依赖性增殖和转移性定殖是必要的。提议项目将检验以下假设：肿瘤细胞簇是高度转移性的，因为它们包含私有涉及EGFR，Epigen和转录因子FRA-1的信号传导环境，并破坏这一点信号环境将中和簇的转移潜力。张实验室已经开发技术创新的器官和鼠模型，以研究基于聚类的信号及其对体内转移。使用这些模型，实验室将首先确定簇诱导的转移效率特别取决于表皮局部激活。其次，实验室将确定FRA-1的影响转录程序和有关肿瘤细胞簇特有的转移过程的信号反馈回路，以及该程序是否取决于表皮的存在。第三，实验室将补充其通过研究EGFR，Epegen和长期复发与长期复发与来自人类乳腺癌数据集的死亡率数据。通过这种综合方法，张实验室将对肿瘤细胞的承诺的基础的合作分子机制发展了解簇转移。如提案中所述，这种理解可能揭示了分子可以探索以开发新的抗转移疗法的漏洞。虽然这项工作是在这里提出的着重于发现靶向乳腺癌肿瘤细胞簇的治疗策略，这些发现将可能与多种肿瘤类型有关。