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（由申请人提供）：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NSCLC，致癌Ras和抑癌基因p53或LKB1的体细胞突变在NSCLC中经常被检测到。不幸的是，直接靶向 Ras、p53 或 LKB1 的有效药物迄今为止尚未成功用于癌症治疗。该项目研究自噬在 Kras 驱动的肺癌中的作用，最终目标是为肺癌治疗提供新策略。自噬是一种保护过程，响应压力而激活，以回收细胞成分以维持体内平衡。在怀特实验室的过去五年中，郭彦翔博士发现，Ras 激活的癌细胞需要自噬来维持功能性线粒体、耐受代谢应激和肿瘤发生。郭博士使用两种用于 Kras 驱动的 NSCLC（有或没有 p53）的基因工程小鼠模型 (GEMM)，并同时删除必需的自噬基因（自噬相关 7、Atg7），发现自噬缺陷改变了 KrasG12D 诱导的癌症的命运，导致罕见的、主要是良性的嗜酸细胞瘤，导致有缺陷的线粒体积累和 减少肿瘤生长。随着 p53 的额外损失，自噬缺陷会损害线粒体脂肪酸氧化 (FAO)，导致脂质稳态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。在这个 NIH 过渡职业发展奖中，郭博士在她的导师 Eileen White 博士和她的合作者的支持下，计划测试自噬对于肺癌代谢和生长很重要的中心假设，具体目标如下： 目标 1 是确定 Atg7 缺陷对肿瘤生长的抑制在多大程度上是可逆的，以及与正常组织相比，自噬抑制如何对肿瘤产生不同的影响；目标 2 是确定在具有 p53 错义突变的 KrasG12D 驱动的 NSCLC 中是否需要自噬来抑制嗜酸细胞瘤形成并维持脂质稳态；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质组学分析将用于确定自噬调节癌症代谢和生长的机制。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，并将识别代谢改变造成的代谢脆弱性。这些发现将为 Kras 驱动的肺癌治疗提供新的转化方法，通过双重抑制 Ras 下游效应通路和自噬。郭博士在杜克大学 Sally Kornbluth 博士的实验室接受了正式的研究培训，专注于癌症中细胞周期和细胞死亡的调节，并获得了博士学位。分子癌症生物学学位。目前，郭博士是新泽西州罗格斯癌症研究所 (RCINJ) White 博士实验室的助理研究教授，她一直在研究自噬在调节 Ras 驱动的癌症代谢中的功能。郭博士的近期和长期职业目标是： 1）成为 NIH 资助的独立研究员，专注于肺癌代谢； 2）在NCI指定的综合性癌症中心或具有优良科研环境的世界一流研究型大学或研究所培养成为专注于肺癌的科学家团队的带头人； 3）确定抗癌药物的新分子靶点。郭博士将通过三个主要部分来实现这些目标： 1）实验室研究：郭博士将在怀特博士的全力支持下执行上述研究计划。她还将得到合作者的支持和指导，其中包括：普林斯顿大学代谢组学领域公认的领导者 Josh Rabinowitz 博士，他使用代谢组学来探究癌症代谢； Yibing Kang 博士是普林斯顿大学癌症转移领域公认的领导者，致力于研究转移的新方法； Arnold Levine 博士是高级研究所和 RCINJ 癌症研究和 p53 生物学领域广受赞誉的领导者，他将阐明 p53 在癌症中的功能和调节； Chan Chang 博士，RCINJ 癌症遗传学研究中使用下一代测序技术的专家；英国剑桥研究所癌症研究中心的 Narita 博士正在生成一种可诱导的 Tet-on-shRNA-Atg5 shRNA 小鼠模型，该模型将提供给郭博士。 2）教学法：郭博士已经并将继续接受Rabinowitz博士团队提供的代谢组学实践培训。她将参加 Seahorse Biosciences 提供的两门课程“入门 XF 培训”和“高级 XT 培训”，使用 Seahorse Bioscience XF 分析仪研究癌细胞代谢。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。她还将获得成田博士的技术建议，以帮助成功生成她提出的 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“自我与机构客观分析研讨会（OASIS）：领导力和专业发展计划”，帮助她发展成为学术界的领导者。