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：
10449465
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449465
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 Cytotoxic Chemotherapy Data 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 Relapse Research Role Signal Transduction Statistical Data Interpretation System Techniques Testing Therapeutic Tomatoes Touch sensation Training Transplantation Universities Xenograft procedure anticancer research base cancer cell cancer type career cell motility cell type chemokine delivery vehicle differential expression genome editing in vivo inhibitor innovation insight lung cancer cell lung small cell carcinoma mouse model new therapeutic target novel novel therapeutics post-doctoral training prevent sequencing platform single-cell RNA sequencing 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.

项目概要/摘要小细胞肺癌 (SCLC) 是一种顽固性癌症，导致 25 万人死亡每年在全球范围内。 SCLC 患者最初对细胞毒性疗法有反应，但几乎没有反应总是会因治疗耐药性疾病而复发。此外，许多患者在确诊后远处器官（包括肝脏）的转移，这是治疗的主要障碍成功的治疗。转移级联涉及癌细胞与许多正常细胞的相互作用细胞类型，被认为提供促转移和抗转移信号。最近的研究有研究表明，内皮细胞（EC）在不同肿瘤的转移中发挥着重要且多样化的作用。癌症类型。然而，我们对分子和细胞之间相互作用的理解肝转移中的 SCLC 细胞和 EC 仍然不完整，并且没有治疗方法可以预防或阻止这些相互作用，这标志着 SCLC 靶向治疗的巨大治疗可能性诊所里的病人。在这项拟议的研究中，我假设 SCLC-EC 相互作用改变了细胞两种细胞类型的状态以及这些变化对于 SCLC 肝转移至关重要。到为了系统地研究 SCLC 细胞和 EC 之间的相互作用，我开发了一种定性记录各种细胞类型之间物理相互作用的创新方法（GFP- 基于 Touching Nexus、G-baToN）。与此同时，我导师的实验室已经产生了体细胞 CRISPR基因组编辑小鼠模型和高通量肿瘤条形码测序我将使用这些平台来解决转移负担、转移播种和克隆问题 SCLC 肝转移的扩展。通过利用所有这些尖端技术，该项目旨在通过研究表征 SCLC 激活的 EC 在 SCLC 肝转移中的作用 CXCLs-CXCR2 轴（目标 1）和其他细胞间相互作用相关 EC 基因的功能（目标 2）。另一方面，该项目还将定量评估EC引起的影响 SCLC 肝转移的变化（目标 3）。总而言之，该项目将发现新的 SCLC 转移的机制见解，建立研究癌症的新策略- 体外和体内基质相互作用，并确定新的治疗可能性以更好地治疗小细胞肺癌患者。