The role of autophagy in Kras-driven lung cancer

自噬在 Kras 驱动的肺癌中的作用

• 批准号: 9321425
• 负责人: Yanxiang Guo
• 金额: $ 20.96万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321425
• 关键词: Ablation; Academia; Adenocarcinoma; Anoikis; Antineoplastic Agents; Autophagocytosis; Back; Benign; Biological Sciences; Biology; CRISPR/Cas technology; Cancer Biology; Cancer Institute of New Jersey; Cancer Patient; Carcinoma; Cell Adhesion; Cell Cycle Regulation; Cell Death; Cell Line; Cell Survival; Comprehensive Cancer Center; Cyst; Defect; Doctor of Philosophy; Environment; Funding; Genes; Genetic Engineering; Genetic study; Genus Hippocampus; Goals; Growth; Homeostasis; Human; Hypoxia; Impairment; Institutes; Institution; Instruction; KRAS2 gene; Knock-out; Laboratories; Laboratory Research; Large Cell Carcinoma; Leadership; Lipids; Lung; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mentors; Metabolic; Metabolic stress; Metabolism; Missense Mutation; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Oncogenic; Organelles; Oxyphilic Adenoma; Pathway interactions; Pharmaceutical Preparations; Pre-Clinical Model; Process; Program Development; Protein p53; Protein-Serine-Threonine Kinases; Proteins; Quality Control; RAS inhibition; Regulation; Research; Research Assistant; Research Personnel; Research Training; Role; STK11 gene; Scientist; Site; Somatic Mutation; Squamous cell carcinoma; Starvation; Stress; Survival Rate; TP53 gene; Testing; Tetanus Helper Peptide; Therapeutic; Training; Transgenic Mice; Transition Career Development Award (K22); Tumor Burden; Tumor Suppression; Tumor-Derived; United States National Institutes of Health; Universities; Woman; adenylate kinase; anticancer research; cancer cell; cancer genetics; cancer subtypes; cancer therapy; career; fatty acid oxidation; gain of function; genetic makeup; inhibition of autophagy; innovation; leadership development; meetings; men; metabolomics; mitochondrial autophagy; mortality; mouse model; mutant; mutational status; neoplastic cell; next generation sequencing; novel; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; professor; public health relevance; response; small hairpin RNA; translational approach; tumor; tumor growth; tumor metabolism; tumorigenesis

 DESCRIPTION (provided by applicant): Lung cancer is the most common cancer and has the highest mortality in the US. Tumor metastasis is the major cause of mortality for non-small-cell lung cancer (NSCLC) patients. About 85%-90% of lung cancers are NSCLC and somatic mutations in oncogenic Ras and the tumor suppressor p53 or LKB1 are frequently detected in NSCLC. Unfortunately effective drugs that directly target Ras, p53 or LKB1 have so far not succeeded for cancer therapy. This project investigates the role of autophagy on Kras-driven lung cancer with the ultimate goal of providing a new strategy for lung cancer therapy. Autophagy is a protective process that is activated in response to stress in order to recycle cellular components to maintain homeostasis. During the last five years in the White laboratory, Dr. (Jessie) Yanxiang Guo discovered that cancer cells with Ras activation require autophagy for maintenance of functional mitochondria, for tolerance of metabolic stress and for tumorigenesis. Using two genetic engineered mouse models (GEMMs) for Kras-driven NSCLC with or without p53 and concurrent deletion of essential autophagy gene, autophagy-related-7, Atg7, Dr. Guo found that autophagy deficiency altered the fate of KrasG12D-induced carcinomas to rare, predominantly benign oncocytomas, caused accumulation of defective mitochondria and reduced the tumor growth. With the additional loss of p53, autophagy deficiency impaired mitochondrial fatty acid oxidation (FAO) resulting in defective lipid homeostasis and exquisite sensitivity to metabolic stress. These results suggest that Ras-driven cancers may be susceptible to autophagy inhibition therapy. In this NIH Transition Career Development Award, Dr. Guo, supported by her mentor Dr. Eileen White and her collaborators, plans to test the central hypothesis that autophagy is important for metabolism and growth of lung cancer in the following specific aims: Aim 1 is to determine the extent to which suppression of tumor growth by Atg7 deficiency is reversible and how autophagy inhibition differentially impacts tumor compared to normal tissue; Aim 2 is to determine if autophagy is required to suppress oncocytoma formation and to maintain lipid homeostasis in KrasG12D-driven NSCLC with p53 missense mutations; and Aim 3 is to determine if and how autophagy inhibition impacts Kras-driven lung cancer metastasis. State-of-the-art metabolomic and lipidomic analysis will be used to determine the mechanism by which autophagy regulates cancer metabolism and growth. This project will develop innovative pre-clinical models to determine the role of autophagy in lung cancer and will identify metabolic vulnerabilities created by the altered metabolism. These findings will provide novel translational approaches for Kras-driven lung cancer therapy by dual inhibition of Ras downstream effector pathways and autophagy. Dr, Guo obtained her formalized research training in Dr. Sally Kornbluth 's laboratory at Duke University where she focused on the regulation of cell cycle and cell death in cancer, earning a Ph.D. degree in Molecular Cancer Biology. Currently, Dr. Guo is an Assistant Research Professor in Dr. White's laboratory at Rutgers Cancer Institute of New Jersey (RCINJ) where she has been studying the function of autophagy in regulating Ras-driven cancer metabolism. Dr. Guo's immediate and long-term career goals are to: 1) become a NIH funded independent investigator focusing on metabolism of lung cancer; 2) develop into a leader of a dedicated group of scientists that focus on lung cancer at an NCI-designated comprehensive cancer center or a world-class research university or institute with an excellent scientific environment; and 3) identify new molecular targets for anti-cancer drugs. Dr. Guo will accomplish these goals with three major components: 1) Laboratory research: Dr. Guo will execute her research plan outlined above with full support from Dr. White. She will also receive support and instruction from her collaborators including: Dr. Josh Rabinowitz, a recognized leader in metabolomics at Princeton University, in the use of metabolomics to interrogate cancer metabolism; Dr. Yibing Kang, a recognized leader in cancer metastasis at Princeton University, in novel approaches to interrogate metastasis; Dr. Arnold Levine, a widely acclaimed leader in cancer research and p53 biology at Institute of Advanced Study and RCINJ, to elucidate p53 function and regulation in cancer; Dr. Chan Chang, an expert in the use of Next Generation Sequencing in the study of genetics of cancer at RCINJ; and Dr. Narita at Cancer Research UK, Cambridge Institute, who is generating an inducible Tet-on-shRNA-Atg5 shRNA mouse model that will be provided to Dr. Guo. 2) Didactics: Dr. Guo has and will continue to receive hands-on metabolomics training provided by Dr. Rabinowitz's group. She will take two courses "Introductory XF Training" and "Advanced XT Training" provided by Seahorse Biosciences to study cancer cell metabolism using a Seahorse Bioscience XF Analyzer. She will receive on-site training from Dr. Kang and join his lab meetings to further develop expertise in tumor metastasis. She will also obtain technical advise from Dr. Narita to help successfully generate the Tet-on-shRNA-Atg7 mouse model she proposed. 3) Professional/Leadership Development: Dr. Guo will attend "The objective Analysis of Self and Institution Seminar (OASIS): Leadership and Professional Development Program" offered by Rutgers University for women to help her develop as a leader in academia.

 描述(申请人提供)：肺癌是美国最常见的癌症，死亡率最高。肿瘤转移是非小细胞肺癌(NSCLC)患者死亡的主要原因。大约85%-90%的肺癌是非小细胞肺癌，在非小细胞肺癌中经常检测到致癌基因RAS和抑癌基因P53或LKB1的体细胞突变。不幸的是，直接针对RAS、P53或LKB1的有效药物到目前为止还没有成功用于癌症治疗。本项目研究自噬在Kras驱动的肺癌中的作用，最终目的是为肺癌治疗提供一种新的策略。自噬是一种保护性的过程，它在应激反应中被激活，以循环细胞成分来维持体内平衡。在怀特实验室的过去五年里，郭彦翔博士(Jessie)发现，RAS激活的癌细胞需要自噬来维持功能线粒体，耐受代谢压力和肿瘤发生。郭博士使用了两种基因工程小鼠模型(GEMM)来研究Kras驱动的NSCLC，无论是否带有P53，并且同时缺失了必要的自噬基因、自噬相关基因-7和ATG7，郭博士发现，自噬缺陷将KrasG12D诱导的癌症转变为罕见的、主要是良性的嗜酸细胞瘤，导致缺陷线粒体积累，减缓肿瘤生长。随着P53的进一步丢失，自噬缺陷损害了线粒体脂肪酸氧化(FAO)，导致脂质平衡缺陷和对代谢应激的高度敏感性。这些结果表明，RAS驱动的癌症可能对自噬抑制疗法敏感。在这次NIH过渡职业发展奖中，郭博士在她的导师艾琳·怀特博士和她的合作者的支持下，计划在下列特定目的下测试自噬对于肺癌的新陈代谢和生长很重要的中心假说：目的1是确定ATG7缺乏对肿瘤生长的抑制在多大程度上是可逆的，以及自噬抑制如何与正常组织相比对肿瘤产生不同的影响；目标2是确定在带有p53错义突变的KrasG12D驱动的NSCLC中是否需要自噬来抑制瘤细胞的形成和维持脂类平衡；目标3是确定自噬抑制是否以及如何影响Kras驱动的肺癌转移。最先进的代谢组学和脂体学分析将被用于确定自噬调节癌症新陈代谢和生长的机制。该项目将开发创新的临床前模型，以确定自噬在肺癌中的作用，并将确定新陈代谢改变造成的代谢脆弱性。这些发现将通过双重抑制RAS下游效应通路和自噬，为Kras驱动的肺癌治疗提供新的翻译方法。郭博士在杜克大学萨利·科恩布鲁斯博士的S实验室接受了正式的研究培训，在那里她专注于癌症细胞周期和细胞死亡的调节，并获得了分子癌症生物学博士学位。目前，郭博士是新泽西州罗格斯癌症研究所怀特博士实验室的助理研究教授，在那里她一直在研究自噬在调节RAS驱动的癌症新陈代谢中的作用。郭博士近期和长期的职业目标是：1)成为NIH资助的专注于肺癌新陈代谢的独立研究员；2)发展成为NCI指定的综合性癌症中心或拥有良好科学环境的世界级研究大学或研究所的专注于肺癌的专门科学家团队的领导者；3)为抗癌药物寻找新的分子靶点。郭博士将通过三个主要部分实现这些目标：1)实验室研究：郭博士将在怀特博士的全力支持下执行她上面概述的研究计划。她还将得到她的合作者的支持和指导，这些合作者包括：乔希·拉比诺维茨博士，普林斯顿大学代谢组学方面的公认领导者，使用代谢组学研究癌症新陈代谢；康一冰博士，普林斯顿大学癌症转移领域公认的领导者，询问转移的新方法；阿诺德·莱文博士，高等研究院和RCINJ癌症研究和p53生物学领域广受赞誉的领导者，阐明癌症中的p53功能和调控；陈·张博士，下一代测序在RCINJ癌症遗传学研究中的使用专家；英国剑桥研究所癌症研究所的成田博士正在制造一种可诱导的Tet-on-shRNA-ATG5 shRNA小鼠模型，该模型将提供给郭博士。2)教学：郭博士已经并将继续接受由拉比诺维茨博士的团队提供的实践代谢组学培训。她将参加由赛马生物科学公司提供的两门课程“XF入门培训”和“高级XT培训”，使用赛马生物科学XF分析仪研究癌细胞新陈代谢。她将接受康博士的现场培训，并参加他的实验室会议，以进一步发展肿瘤转移方面的专业知识。她还将从成田博士那里获得技术建议，以帮助成功地产生她提出的Tet-on-shRNA-ATG7小鼠模型。3)专业/领导力发展：郭博士将参加罗格斯大学为女性提供的“客观分析自我与机构研讨会(OASIS)：领导力与专业发展计划”，帮助她在学术界发展为领导者。