Defining Early Escape Strategies in LKB1 Mutant Lung Cancer S1

定义 LKB1 突变型肺癌 S1 的早期逃逸策略

• 批准号: 9462511
• 负责人: Melissa GILBERT-ROSS
• 金额: $ 3.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-16 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9462511
• 关键词: 3-Dimensional; Address; Adhesions; Agreement; Animal Model; Basement membrane; Biological; Cancer Model; Cancer Patient; Cell Adhesion; Cell Polarity; Cells; Cellular Metabolic Process; Clinical; Collagen; Collagen Fiber; Data; Drosophila genus; Drosophila melanogaster; Epithelial; Epithelium; Exhibits; Extracellular Matrix; Family member; Focal Adhesion Kinase 1; Genes; Genetic; Genetic Engineering; Goals; Human; In Vitro; Invaded; KRAS2 gene; Link; Lung Adenocarcinoma; Lung Neoplasms; Malignant neoplasm of lung; Mesenchymal; Metastatic Neoplasm to the Lung; Modeling; Mosaicism; Mus; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Phenotype; Phosphotransferases; Primary Neoplasm; Protein-Serine-Threonine Kinases; Proteomics; Publishing; Regulation; Reporting; STK11 gene; Signal Pathway; Signal Transduction; Signaling Molecule; System; Testing; Time; Tumor Bank; Tumor Initiators; Tumor stage; Work; base; cancer cell; cell motility; defined contribution; in vivo; innovation; mouse model; mutant; neoplastic cell; novel; public health relevance; sequencing platform; targeted treatment; tumor; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): The 3rd most commonly mutated gene in lung adenocarcinoma is the kinase LKB1 (STK11), where ~25,000 patients have this mutation. Patients that are co-mutated for LKB1 and KRAS have significantly shorter overall survival compared to either mutation alone and have no effective targeted therapies. In a genetically engineered Kras mouse model, co-mutation of Lkb1 is sufficient to promote metastasis of lung adenocarcinoma, and primary tumors and metastases show aberrant activation of both EMT and adhesion signaling. In agreement with these data, we have published three reports that LKB1 regulates lung cancer motility and when present, restrict the activity of a key adhesion signaling molecule, focal adhesion kinase (FAK). Moreover, our preliminary data show that Lkb1-deficient tumor cells invade as a collective pack in vivo, and in doing so, remodel the collagen ECM of the tumor microenvironment, a phenomenon that is dependent on the activity of FAK in vitro. These metastatic tumors from the mouse model show aberrant FAK activation within collective invasion packs of the primary tumors. Therefore, we hypothesize that LKB1-mutant cells use EMT to initially invade through the basement membrane, which is followed by defective FAK-based adhesion signaling that allows cells to navigate the collagen microenvironment during metastasis. To test this, we will take a multi-model approach that combines the power of Drosophila and mouse genetics, and our large clinically annotated human lung adenocarcinoma tumor bank to i) test the mechanism and signaling pathway used by Lkb1-mutant cells to traverse the basement membrane, ii) determine whether altered adhesion signaling drives in vivo cell escape through collagen remodeling, and iii) determine whether LKB1-mutant human lung adenocarcinoma exhibits altered adhesion signaling that correlates with collagen remodeling and predicts poor outcome. We propose that this comprehensive approach can overcome the shortcomings of traditional in vitro systems and address our goal of defining the biological consequences of LKB1 mutations in lung cancer patients.

 描述（由申请人提供）：肺腺癌中第三个最常见的突变基因是激酶 LKB1 (STK11)，大约 25,000 名患者有这种突变。与单独突变相比，LKB1 和 KRAS 共突变患者的总生存期显着缩短，并且没有有效的靶向治疗。在基因工程 Kras 小鼠模型中，Lkb1 的共突变足以促进肺腺癌的转移，并且原发性肿瘤和转移瘤显示 EMT 和粘附信号传导的异常激活。与这些数据一致，我们发表了三份报告，表明 LKB1 调节肺癌运动，并且当存在时，限制关键粘附信号分子、粘着斑激酶 (FAK) 的活性。此外，我们的初步数据表明，Lkb1缺陷的肿瘤细胞在体内作为集体入侵，并在此过程中重塑肿瘤微环境的胶原ECM，这种现象依赖于体外FAK的活性。这些来自小鼠模型的转移性肿瘤在原发性肿瘤的集体侵袭包内显示出异常的 FAK 激活。因此，我们假设 LKB1 突变细胞首先利用 EMT 侵入基底膜，然后是基于 FAK 的有缺陷的粘附信号传导，使细胞在转移过程中能够在胶原微环境中导航。为了测试这一点，我们将采用一种多模型方法，结合果蝇和小鼠遗传学的力量，以及我们大型临床注释的人肺腺癌肿瘤库，以i）测试Lkb1突变细胞穿越基底膜的机制和信号通路，ii）确定改变的粘附信号是否通过胶原重塑驱动体内细胞逃逸，以及iii）确定是否 LKB1 突变的人肺腺癌表现出与胶原重塑相关的粘附信号改变，并预测不良结果。我们认为这种综合方法可以克服传统体外系统的缺点，并实现我们确定 LKB1 突变对肺癌患者的生物学后果的目标。