Modeling tumor-stroma crosstalk in lung cancer to identify targets for therapy

模拟肺癌中的肿瘤-基质串扰以确定治疗靶点

• 批准号: 9308914
• 负责人: Vivek Mittal
• 金额: $ 41.2万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-02 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308914
• 关键词: Address; Autocrine Communication; Beds; Biology; Bone Marrow; Cancer Patient; Candidate Disease Gene; Cells; Clinic; Clinical; Clinical Trials; Complement; Computer Simulation; Computer software; Data; Development; Dimensions; Drug Targeting; Drug-sensitive; Employee Strikes; Encapsulated; Endothelial Cells; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Epithelial Cells; Erlotinib; Gefitinib; Genes; Genetic; Genetically Engineered Mouse; Growth; Harvest; Human; Impairment; In Vitro; Individual; Infiltration; Ligands; Lung; MMP14 gene; Malignant neoplasm of lung; Mediating; Modeling; Mus; Mutation; Myelogenous; Myeloid Cells; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Pharmacology; RNA; Receptor Protein-Tyrosine Kinases; Resistance; Role; Signal Pathway; Signal Transduction; Software Tools; Source; Specimen; Stromal Cells; Study models; Therapeutic; Tissues; Treatment Efficacy; Validation; Visualization software; autocrine; base; cancer cell; carcinogenesis; cell stroma; cell type; conventional therapy; crizotinib; deep sequencing; design; genome wide association study; improved; in vitro Assay; inhibitor/antagonist; insight; kinase inhibitor; macrophage; molecular targeted therapies; monocyte; mouse model; neoplastic cell; network models; neutrophil; novel; novel therapeutics; paracrine; public health relevance; receptor; targeted treatment; therapeutic target; therapy resistant; transcriptome; transcriptome sequencing; treatment response; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): There is an unmet need for molecularly targeted therapies for the treatment of non-small cell lung cancer (NSCLC). Taking into account the emerging paradigm that the reprogrammed intratumoral stromal cells contribute to carcinogenesis, we have employed integrated experimental and computational approaches to identify tumor-stroma crosstalk pathways that drive NSCLC progression. To explore paracrine/autocrine crosstalk, we performed RNA deep sequencing analysis of specific cellular myeloid and epithelial compartments isolated from freshly harvested lungs of NSCLC patients, and a genetically engineered mouse model of NSCLC. We compared transcriptomes of intratumoral myeloid cells (monocytic, neutrophils and macrophages) and tumor epithelial cells with their counterparts within matched adjacent non-neoplastic tissue. In this application, we will develop a multi-cellular crosstalk signaling network modeling and visualization software tool (Aim 1) and apply this model to multi-cellular RNA-seq data to identify tumor-stroma crosstalk pathways; genes involved in these signaling mechanisms will be considered potential candidates that mediate NSCLC tumor progression and will undergo rapid validation using in vitro assays (Aim 2). Finally, we will determine the function of selected crosstalk pathways in NSCLC progression and in mediating therapeutic resistance (Aim 3). In summary, this study explores the relatively understudied tumor-stroma crosstalk pathways as a largely untapped source of drug targets and has tremendous potential for the development of novel therapeutic strategies that target tumor-stroma interactions and may complement existing treatments that target cancer cells.

 描述(由申请人提供)：非小细胞肺癌(NSCLC)的分子靶向治疗需求尚未得到满足。考虑到重新编程的肿瘤内基质细胞有助于癌症发生的新范式，我们采用了综合的实验和计算方法来识别驱动非小细胞肺癌进展的肿瘤-基质串扰通路。为了探索旁分泌/自分泌串扰，我们对从NSCLC患者新鲜肺和一个基因工程小鼠模型肺中分离出的特定细胞髓系和上皮细胞进行了RNA深度测序分析。我们比较了瘤内髓系细胞(单核细胞、中性粒细胞和巨噬细胞)和肿瘤上皮细胞与匹配的邻近非肿瘤组织中的相应细胞的转录。在此应用程序中，我们将 开发多细胞串扰信号网络建模和可视化软件工具(AIM 1)，并将该模型应用于多细胞RNA-SEQ数据，以确定肿瘤-间质串扰通路；参与这些信号机制的基因将被认为是介导非小细胞肺癌肿瘤进展的潜在候选基因，并将使用体外分析进行快速验证(AIM 2)。最后，我们将确定选定的串扰通路在非小细胞肺癌进展和调节治疗耐药中的功能(目标3)。总而言之，这项研究探索了相对研究较少的肿瘤-间质串扰通路，作为一个基本上未被开发的药物靶点来源，并具有巨大的潜力开发针对肿瘤-间质相互作用的新治疗策略，并可能补充现有的针对癌细胞的治疗。