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Transcriptional Regulation of Lung Cancer Identity

肺癌身份的转录调控

基本信息

批准号：
10583302
负责人：
Eric Lee Snyder
金额：
$ 38.43万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583302
关键词：
Adenocarcinoma Cell Adopted Automobile Driving Biological Cancer Etiology Cell Line Cell Lineage Cells Cessation of life ChIP-seq Chief Cell Chromatin Clinical Complex Data Dependence Diagnosis Disease Drug Tolerance Drug resistance Epigenetic Process Equilibrium Exhibits Gastric Chief Cells Genetic Transcription Genetically Engineered Mouse Goals Growth Heterogeneity Histologic Human Impairment Knowledge LGR5 gene Lung Lung Adenocarcinoma Malignant neoplasm of lung Modeling Molecular Morphology Mucous Membrane Oncogenic Organoids Pathway interactions Phosphorylation Predisposition Primary Neoplasm Proliferating Publishing Regulation Research Residual Neoplasm Residual state Resistance Role Signal Pathway Signal Transduction Specific qualifier value Stomach Surface Testing Therapeutic Time Transcriptional Regulation WNT Signaling Pathway Work acquired drug resistance actionable mutation cancer cell cell type clinically relevant design disorder subtype epigenomic profiling gastrointestinal human model inhibitor mouse model neoplastic cell novel patient derived xenograft model patient prognosis pharmacologic programs targeted treatment transcriptome sequencing tumor heterogeneity tumor progression tumorigenesis tumorigenic

项目摘要

Project Summary Lung adenocarcinoma, the most common cause of cancer death worldwide, exhibits substantial heterogeneity in cellular identity, or differentiation state. In this disease, cancer cell identity correlates with critical clinical parameters, including patient prognosis, intrinsic sensitivity to therapy, and acquisition of drug resistance. Thus, there is an unmet need to obtain a comprehensive understanding of mechanisms controlling LUAD identity. A major rationale for this proposal is that a mechanistic understanding of the complex interplay between lineage specifiers and oncogenic signaling pathways in LUAD must be achieved before such therapeutic strategies can be developed. The immediate goal of this application is to test the central hypothesis that lineage specifiers and oncogenic signaling pathways coordinately modulate LUAD identity and growth. This hypothesis will be tested in the following specific aims via an integrative experimental approach employing genetically engineered mouse models (GEMMs), organoid cultures, human PDX models/cell lines and clinically relevant pathway inhibitors: (1) Identify mechanisms by which FoxA1/2 promote tumorigenesis and activate a mixed-lineage state in NKX2-1-positive lung adenocarcinoma. (2) Identify mechanisms by which oncogenic signaling pathways regulate identity in NKX2-1-negative lung adenocarcinoma.

项目摘要肺腺癌是全世界最常见的癌症死亡原因，处于细胞身份或分化状态。在这种疾病中，癌细胞的身份与关键的临床参数，包括患者预后、对治疗的内在敏感性和耐药性的获得。因此，需要全面了解控制LUAD的机制身份这一建议的一个主要理由是，对复杂相互作用的机械理解 LUAD中的谱系特异性和致癌信号通路之间的联系必须在这种联系之前实现。可以开发治疗策略。这个应用程序的直接目标是测试中心假设谱系特异性和致癌信号通路协调调节LUAD的身份和生长。这一假设将通过综合实验方法在以下具体目标中进行测试，基因工程小鼠模型（GEMM）、类器官培养物、人PDX模型/细胞系和临床相关通路抑制剂：（1）确定FoxA 1/2促进肿瘤发生和激活肿瘤细胞的机制。 NKX 2 -1阳性肺腺癌的混合谱系状态。(2)确定致癌的机制，信号通路调节NKX 2 -1阴性肺腺癌的身份。