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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。通过剖析驱动它的分子事件