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.

项目摘要 /摘要 小细胞肺癌（SCLC）是一种顽固性癌症，可导致250,000人死亡 每年全球。 SCLC患者最初对细胞毒性疗法有反应，但几乎 抗治疗疾病总是复发。而且，当被诊断出时，许多患者有 包括肝脏在内的远处器官中的转移，这代表了对 成功的治疗。转移性级联反应涉及许多正常的癌细胞相互作用 细胞类型被认为是由促和抗转移信号提供的。最近的研究 表明内皮细胞（EC）在不同的转移中起重要而多样的作用 癌症类型。但是，我们对分子和细胞相互作用之间的理解 肝转移中的SCLC细胞和EC仍然不完整，没有疗法来预防或 停止这些相互作用，这标志着SCLC的目标治疗的极大治疗可能性 诊所的患者。在这项拟议的研究中，我假设SCLC-EC相互作用改变了细胞 两种细胞类型和这些变化的状态对于SCLC肝转移至关重要。到 从系统地研究SCLC细胞与EC之间的相互相互作用，我已经开发了一个 创新方法是在定性地记录各种细胞类型之间的物理相互作用（GFP- 基于触摸Nexus，G-Baton）。同时，我的导师的实验室已经产生了躯体 CRISPR基因组编辑鼠标模型和高通量肿瘤条形码测序 我将采用的平台去宣传转移性负担，转移性播种和克隆 SCLC肝转移的扩张。通过利用所有这些尖端技术，这个项目 旨在通过研究来表征SCLC激活EC在SCLC肝转移中的作用 CXCLS-CXCR2轴的功能（AIM 1）和其他与细胞相互作用相关的EC基因的功能 （目标2）。另一方面，该项目还将定量评估EC诱导的影响 SCLC转移中的SCLC交替（AIM 3）。综上所述，这个项目将发现新的 SCLC转移中的机械见解，建立了研究癌症的新策略 - 体外和体内的基质相互作用，并确定新的治疗可能性以更好地治疗 SCLC患者。