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。

• 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
• 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

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.

项目总结/摘要 小细胞肺癌（SCLC）是一种恶性肿瘤，导致25万人死亡 全球每年都有。SCLC患者最初对细胞毒性疗法有反应，但几乎所有的SCLC患者都对细胞毒性疗法有反应。 总是会复发，并伴有耐药疾病。此外，在诊断时，许多患者 包括肝脏在内的远处器官的转移，这是转移的主要障碍。 成功的治疗转移级联反应涉及癌细胞与许多正常细胞的相互作用。 细胞类型，这被认为是提供促和抗转移信号。最近的研究 显示内皮细胞（EC）在不同肿瘤的转移中发挥重要和不同的作用， 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仍然是不完整的，并且不存在预防或治疗SCLC细胞和EC的疗法。 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 这两种细胞类型的状态和这些变化是SCLC肝转移的关键。到 为了系统研究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 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卷积转移负荷、转移播种和克隆， 小细胞肺癌肝转移扩大。通过利用所有这些尖端技术，这个项目 旨在通过研究SCLC激活的EC在SCLC肝转移中的作用， CXCLs-CXCR 2轴（Aim 1）和其他细胞-细胞相互作用相关EC基因的功能 (Aim 2）。另一方面，该项目还将定量评估EC引起的影响 SCLC在肝转移中的变化（目的3）。总的来说，这个项目将揭示新的 SCLC转移机制的见解，建立新的研究癌症的策略， 基质相互作用在体外和体内，并确定新的治疗可能性，以更好地治疗 SCLC患者