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）：胸腔恶性肿瘤是大多数与癌症有关的死亡。最常见的肺癌亚型是肺腺癌（LUAD），它显示出显着的生物异质性和预后不良。 LUAD的一部分在分化状态下迅速分歧，与治疗性耐药性和转移性复发有关。尽管最近在人类肺癌的基因组分类方面取得了进步，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，我们发现了一种新的途径，该途径通过谱系转录因子Hopx抑制了LUAD细胞的转移性倾向。 HOPX不仅可以指导肺泡分化，而且还通过抑制营养感应激酶GCN2的活性（一般对照2）及其对氨基酸生物合成的下游控制来限制代谢应力反应。我们假设抑制HOPX Primes高级LUAD细胞以激活一种代谢途径，该途径可以预先基础，以进行后续转移。我们将此途径称为谱系定向自适应应力反应（LASR），并预测它将增加LUAD细胞对各种转移性壁ni的适应能力。我们的假设将通过整合生物信息学，分子，代谢组和生物学方法来研究。在AIM 1中，我们将确定在LUADS中激活LASR的转录机制，并确定其与人类生物测量中临床结果的相关性。在AIM 2中，我们将通过对循环和细胞外基质中代谢和微环境应激的条件进行建模，确定转移性LUAD细胞中关键LASR酶效应子的功能。我们还将对天冬氨酸和丝氨酸进行代谢通量分析，这是两个氨基酸的分解代谢，预计是luad细胞传播所必需的及其因休眠而出现的。在AIM 3中，我们将表征在体内LUAD分化，进展和转移性定植期间对LASR的需求。为此，我们将使用我们已建立的人类LUAD的异种移植模型以及一种互补的基因工程小鼠模型中的新型靶向方法，采用时空控制的功能方法的增益或丧失。我们的发现揭示了上皮代谢适应在肺部发育计划的直接控制之下。这种新型途径的放松管制还为某些早期肺癌转移的风险升高提供了一种有力的机制。最后，我们的建议将对氨基酸代谢和蛋白质抗体的前瞻性治疗学如何有效地利用用于辅助治疗和/或晚期转移治疗的有效性。