A novel lineage pathway controls metabolic adaptation by metastatic lung cancers

一种新的谱系途径控制转移性肺癌的代谢适应

基本信息

批准号：
9182876
负责人：
Don X Nguyen
金额：
$ 38.03万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9182876
关键词：
Acute Adenocarcinoma Cell Adjuvant Therapy Affect Aggressive Clinical Course Alpha Cell Alveolar Amino Acids Amino Acids Activation Anabolism Anoikis Apoptosis Asparagine Aspartate-Ammonia Ligase Attenuated Bioenergetics Biogenesis Bioinformatics Biological Biological Process Biological Response Modifier Therapy Biology Blood Circulation Cancer Patient Catabolism Cataloging Catalogs Cell Lineage Cell Survival Cell model Cells Cellular Metabolic Process Cessation of life Clinical Competence Consumption Coupled Development Disease Distant Enzymes Epithelial Exposure to Extracellular Matrix Gene Delivery Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomics Homeostasis Human Human Genome Hypoxia Link Lung Lung Adenocarcinoma Lung Capacity Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thorax Metabolic Metabolic Control Metabolic Pathway Metabolic stress Modeling Molecular Morphogenesis Mutation Neoplasm Metastasis Nutrient Organ Outcome Pathway interactions Patients Phosphotransferases Physiological Relapse Repression Resected Residual Neoplasm Risk Role Serine Source Starvation Stress TP53 gene Therapeutic Tissues Transcription Coactivator Transfer RNA Xenograft Model Xenograft procedure amino acid metabolism aminoacid biosynthesis biological adaptation to stress biological heterogeneity cancer cell cancer subtypes cell type detection of nutrient enzyme biosynthesis extracellular human tissue in vivo innovation insight interdisciplinary approach knock-down loss of function metabolomics mouse model novel outcome forecast programs prospective proteostasis public health relevance response sensor therapeutic target therapy resistant transcription factor tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Thoracic malignancies account for the majority of cancer-related deaths. The most frequent lung cancer subtype is lung adenocarcinoma (LuAd), which displays remarkable biological heterogeneity and poor prognosis. A subset of LuAds rapidly diverge in their differentiation states, correlating with therapeutic resistance and metastatic relapse. Despite recent advances in cataloguing the genome of human lung cancers, the molecular and biological determinants of LuAd metastasis remain poorly understood. By employing innovative genomics and experimental approaches, we uncovered a molecular link between LuAd metastasis, airway epithelial specification, and metabolic reprogramming. In particular, we discovered a novel pathway that suppresses the metastatic proclivity of LuAd cells through the lineage transcription factor HOPX. HOPX not only directs alveolar differentiation, but also constrains a metabolic stress response by inhibiting the activity of the nutrient sensing kinase GCN2 (general control nonrepressed 2) and its downstream control of amino acid biosynthesis. We hypothesize that the suppression of HOPX primes high-grade LuAd cells to activate a metabolic pathway that pre-conditions them for subsequent metastasis. We refer to this pathway as a Lineage directed Adaptive Stress Response (LASR) and predict that it will increase the adaptive capacity of LuAd cells for various metastatic niches. Our hypothesis will be studied by integrating bioinformatics, molecular, metabolomic, and biological approaches. In Aim 1, we will determine the transcriptional mechanism by which the LASR is activated in LuAds and ascertain its correlation with clinical outcome in human biospecimens. In Aim 2, we will determine the function of key LASR enzymatic effectors in metastatic LuAd cells, by modeling conditions of metabolic and microenvironmental stress in circulation and the extracellular matrix. We will also perform a metabolic flux analysis of asparagine and serine, two amino acids whose catabolism is predicted to be required for LuAd cell dissemination and their emergence from dormancy. In Aim 3, we will characterize the requirement for the LASR during LuAd differentiation, progression, and metastatic colonization in vivo. To this end, we will employ spatio-temporally controlled gain or loss of function approaches, using our established xenograft model of human LuAd as well as a novel targeting approach in a complementary genetically engineered mouse model. Our findings reveal how epithelial metabolic adaptation is under the direct control of developmental programs in the lungs. The deregulation of this novel pathway also provides a cogent mechanism for the elevated risk of certain early stage lung cancers to metastasize. Finally, our proposal will generate significant insight as to how prospective therapeutics directed against amino acid metabolism and proteostasis can be effectively harnessed for adjuvant therapy and/or the treatment of late stage metastasis.

描述（由申请人提供）：胸部恶性肿瘤占癌症相关死亡的大部分。最常见的肺癌亚型是肺腺癌（LuAd），其表现出显着的生物学异质性和不良预后。 LuAd 的一个子集在分化状态上迅速分化，与治疗耐药和转移复发相关。尽管最近在人类肺癌基因组编目方面取得了进展，但 LuAd 转移的分子和生物学决定因素仍然知之甚少。通过采用创新的基因组学和实验方法，我们发现了 LuAd 转移、气道上皮规范和代谢重编程之间的分子联系。特别是，我们发现了一种通过谱系转录因子 HOPX 抑制 LuAd 细胞转移倾向的新途径。 HOPX 不仅指导肺泡分化，还通过抑制营养感应激酶 GCN2（一般控制非抑制 2）及其下游氨基酸生物合成控制的活性来限制代谢应激反应。我们假设 HOPX 的抑制会促使高级 LuAd 细胞激活代谢途径，为随后的转移做好准备。我们将此途径称为谱系定向适应性应激反应（LASR），并预测它将提高 LuAd 细胞对各种转移生态位的适应能力。我们的假设将通过整合生物信息学、分子、代谢组学和生物学方法来研究。在目标 1 中，我们将确定 LuAds 中 LASR 激活的转录机制，并确定其与人类生物样本临床结果的相关性。在目标 2 中，我们将通过模拟循环和细胞外基质中的代谢和微环境应激条件，确定转移性 LuAd 细胞中关键 LASR 酶效应子的功能。我们还将对天冬酰胺和丝氨酸进行代谢流分析，这两种氨基酸的分解代谢预计是 LuAd 细胞传播及其从休眠状态中苏醒所必需的。在目标 3 中，我们将描述 LuAd 分化、进展和体内转移定植过程中对 LASR 的需求。为此，我们将采用时空控制的功能获得或丧失方法，使用我们建立的人类 LuAd 异种移植模型以及互补基因工程小鼠模型中的新型靶向方法。我们的研究结果揭示了上皮代谢适应如何受到肺部发育程序的直接控制。这种新途径的放松管制也为某些早期肺癌转移风险的升高提供了一个令人信服的机制。最后，我们的建议将对如何有效利用针对氨基酸代谢和蛋白质稳态的前瞻性疗法进行辅助治疗和/或晚期转移的治疗产生重要的见解。