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

• 批准号: 8984877
• 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
• 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/8984877
• 关键词: Accounting; Acute; Adenocarcinoma Cell; Adjuvant Therapy; Affect; Aggressive Clinical Course; Alveolar; Amino Acids; Amino Acids Activation; 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; Health; Homeostasis; Human; Human Genome; Hypoxia; Link; Lung; Lung Adenocarcinoma; 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; RNA, Transfer, Amino Acid-Specific; Relapse; Repression; Resected; Residual Neoplasm; Risk; Role; Serine; Source; Staging; 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; knock-down; loss of function; metabolomics; mouse model; novel; outcome forecast; programs; prospective; response; sensor; therapeutic target; therapy resistant; transcription factor; tumor; tumor microenvironment; tumor progression; tumorigenesis

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(申请人提供)：胸部恶性肿瘤占癌症相关死亡的大部分。肺腺癌(LuAd)是最常见的肺癌亚型，其生物学异质性显著，预后不良。LuAD的一个子集在其分化状态下迅速分化，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。通过使用创新的基因组学和实验方法，我们揭示了LuAd转移、呼吸道上皮规范和代谢重新编程之间的分子联系。特别是，我们发现了一条通过谱系转录因子HOPX抑制LuAd细胞转移倾向的新途径。HOPX不仅指导肺泡分化，而且通过抑制营养传感蛋白GCN2的活性(一般控制非抑制2)及其下游的氨基酸生物合成来抑制代谢应激反应。我们假设，HOPX的抑制启动了高级别的LuAd细胞，激活了一条代谢途径，为它们的后续转移奠定了基础。我们将这一途径称为谱系导向的适应性应激反应(LASR)，并预测它将增加LuAd细胞对各种转移小生境的适应能力。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LASR在LuAds中被激活的转录机制，并确定其与人类生物显微镜临床结局的相关性。在目标2中，我们将通过模拟循环和细胞外基质中代谢和微环境应激的条件，确定关键的LASR酶效应因子在转移性LuAd细胞中的功能。我们还将进行天冬酰胺和丝氨酸的代谢流量分析，这两种氨基酸的分解代谢被预测为LuAd细胞扩散和从休眠中苏醒所必需的。在目标3中，我们将描述LuAd在体内分化、进展和转移定植过程中对LASR的要求。为此，我们将采用时空可控的功能获得或丧失方法，使用我们建立的人LuAd异种移植模型，以及在互补的基因工程小鼠模型中的新靶向方法。我们的发现揭示了上皮代谢适应是如何受到肺部发育程序的直接控制的。这一新途径的解除也为某些早期肺癌转移风险的增加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地利用针对氨基酸代谢和蛋白平衡的前瞻性治疗方法进行辅助治疗和/或晚期转移的治疗提供重要的见解。