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Dissecting reciprocal interactions between cancer cells and endothelial cells in SCLC liver metastasis.

剖析 SCLC 肝转移中癌细胞和内皮细胞之间的相互作用。

基本信息

批准号：
10592328
负责人：
Rui Tang
金额：
$ 15.61万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592328
关键词：
Angiogenesis Inhibitors Automobile Driving CRISPR screen CXCL1 gene Cancer Etiology Cancer Patient Candidate Disease Gene Cell Communication Cell Culture System Cell Surface Proteins Cell physiology Cells Cessation of life Clinic Clinical Clonal Expansion Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Cytotoxic Chemotherapy Data Dedications Diagnosis Disease Resistance Disseminated Malignant Neoplasm Distant Endothelial Cells Environment Exposure to Family Future Gene Expression Alteration Gene Expression Profile Gene Mutation Genes Genetically Engineered Mouse Genotype Human Cell Line IL8RB gene In Vitro Isogenic transplantation Liver Malignant Neoplasms Malignant neoplasm of lung Mentors Metastatic Neoplasm to the Liver Methodology Methods Modeling Molecular Mus Neoplasm Metastasis Normal Cell Oncogenes Organ Patients Phase Play Population Positioning Attribute Proliferating Relapse Research Role Signal Transduction Statistical Data Interpretation System Techniques Testing Therapeutic Tomatoes Touch sensation Training Transplantation Universities Xenograft procedure anticancer research cancer cell cancer type career cell motility cell type chemokine delivery vehicle differential expression genome editing in vivo inhibitor innovation insight lung cancer cell mouse model new therapeutic target novel novel therapeutics post-doctoral training prevent sequencing platform single-cell RNA sequencing small cell lung carcinoma targeted treatment therapy resistant three dimensional cell culture transcriptome sequencing transplant model tumor tumor barcoding and sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT Small cell lung cancer (SCLC) is a recalcitrant cancer that causes 250,000 deaths worldwide each year. Patients with SCLC initially respond to cytotoxic therapies but almost invariably relapse with therapy resistant disease. Moreover, when diagnosed, many patients have metastases in distant organs including the liver, which represents a major impediment to successful therapy. The metastatic cascade involves cancer cell interactions with many normal cell types, which are thought to provide by pro- and anti-metastatic signals. Recent studies have shown that endothelial cells (ECs) play important and diverse roles in metastasis of different cancer types. However, our understanding of the molecular and cellular interactions between SCLC cells and ECs in liver metastasis remains incomplete and no therapies exist to prevent or stop these interactions, which marks great therapeutic possibilities for target treatment for SCLC patients in clinic. In this proposed study, I hypothesize that SCLC-EC interactions alter the cell state of both cell types and these changes are critical for SCLC liver metastasis. To systemically study the reciprocal interactions between SCLC cells and ECs, I have developed an innovative method to qualitatively record physical interactions between various cell types (GFP- based Touching Nexus, G-baToN). Meanwhile, my mentors' labs have generated somatic CRISPR genome editing mouse models and high-throughput tumor barcode sequencing platforms which I will employ to deconvolute metastatic burden, metastatic seeding, and clonal expansion in SCLC liver metastasis. By leveraging all these cutting-edge techniques, this project aims to characterize the role of SCLC-activated ECs in SCLC liver metastasis through studying the function of the CXCLs-CXCR2 axis (Aim 1) and other cell-cell interaction related EC genes (Aim 2). On the other hand, this project will also quantitatively assess the impact of EC-induced SCLC alternations in liver metastasis (Aim 3). Taken together, this project will uncover new mechanistic insights in SCLC metastasis, establish new strategies for investigating cancer- stromal interactions in vitro and in vivo, and identify new therapeutic possibilities to better treat SCLC patients.

项目摘要/摘要