Elucidate the mechanism of autophagy in supporting Lkb1-deficient lung tumorigenesis and metastasis

阐明自噬支持 Lkb1 缺陷型肺肿瘤发生和转移的机制

• 批准号: 9885542
• 负责人: Yanxiang Guo
• 金额: $ 37.64万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9885542
• 关键词: 5' -AMP-activated protein kinase; Ablation; Accounting; Address; Adenocarcinoma; Adenocarcinoma Cell; Autophagocytosis; Biological Models; Bypass; Cancer Etiology; Cancer Patient; Catabolic Process; Cell Proliferation; Cell Survival; Cells; Clinical Trials; Essential Genes; Frequencies; Genes; Genetic Predisposition to Disease; Genetically Engineered Mouse; Goals; Homeostasis; Impairment; In Vitro; KRAS2 gene; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolic stress; Metabolism; Metastatic Neoplasm to the Lung; Mus; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nutrient; Oncogenic; Organelles; Patients; Play; Process; Property; Proteins; Resistance; Role; STK11 gene; Squamous cell carcinoma; Starvation; TP53 gene; Testing; Therapeutic; Transition Career Development Award (K22); base; cancer cell; cancer therapy; exome sequencing; extracellular; fatty acid metabolism; genome-wide; improved; in vivo; inhibition of autophagy; insight; knock-down; lipid metabolism; loss of function; lung tumorigenesis; mortality; mouse model; mutant; neoplastic cell; novel; outcome forecast; pre-clinical; predictive marker; response; targeted treatment; transdifferentiation; tumor; tumor growth; tumor initiation; tumor metabolism; tumorigenesis

Abstract Lung cancer is the leading cause of cancer mortality, with non-small cell lung cancer (NSCLC) accounting for more than 85% of these cases. KRAS, the most common oncogenic driver in NSCLC, confers a poor prognosis with limited treatment options. LKB1 is the third most frequently mutated gene in NSCLC. The mutations in both KRAS and LKB1 account for about 30% of NSCLC, with increased aggressiveness, a high frequency of metastases and resistance to therapeutics. Autophagy degrades proteins and organelles and recycles them to provide metabolic substrates, a function that is critical when extracellular nutrients are limited. Although the role of autophagy in cancer has been intensively studied, the precise role of autophagy in cancer, especially in vivo, remains elusive and controversial. Moreover, targeting autophagy to treat cancer generally has not contributed significantly to the advancement of clinical trials. Therefore, identifying genetic vulnerability that renders strong sensitivity to autophagy inhibition is urgently needed to improve autophagy targeted- therapies. LKB1 regulates energy homeostasis by activating AMP-activated protein kinase (AMPK), which inhibits catabolic processes and upregulates anabolic processes, in response to energy crisis. Based on earlier studies, we began to test the hypothesis that loss of LKB1 promotes cancer cell proliferation but also restricts adaptation to metabolic stress, a property that may be further compromised by loss of autophagy. Using genetically engineered mouse models (GEMMs) of NSCLC, we found that autophagy inhibition was synthetically lethal in KrasG12D/+;Lkb1-/- (KL) mediated tumorigenesis; in contrast to KL lung tumors with intact autophagy, loss of an essential autophagy gene, Atg7, dramatically impaired both tumor initiation and tumor growth. This is in sharp contrast to wild-type LKB1 (KrasG12D/+;p53-/-) tumors that are much less sensitive to essential autophagy gene ablation. Our in vitro study further revealed that autophagy modulates lipid metabolism essential for KL cancer cells to survive nutrient starvation. These observations indicate that LKB1 mutations predispose KRAS- driven NSCLC to autophagy inhibition and that LKB1 mutations could be explored as a predictive biomarker for precision lung cancer therapy. Based on our recent findings, we form our central hypothesis: autophagy compensates for LKB1 loss by maintaining the metabolism of Lkb1-deficient Kras-driven lung tumors and promoting their metastasis. We will test this with following specific aims: Aim 1. Elucidate the mechanism by which autophagy regulates lipid metabolism and KL tumorigenesis in vivo. Aim 2. Determine how autophagy promotes KL tumor metastasis. Aim 3. Identify metabolic bypasses that potentially create resistance to autophagy inhibition in KL NSCLC. Successful completion of this proposal will: (1) yield new insights into the role of autophagy in modulating cellular metabolism in support of KL lung tumorigenesis and metastasis; (2) validate the novel concept that autophagy inhibition is a selective and powerful therapeutic strategy against primary and metastatic KL NSCLC; and (3) reveal metabolic bypass as a potential mechanism of therapy resistance.

肺癌是非小细胞肺癌（NSCLC）是导致癌症死亡的主要原因。