Role of MUC5AC in promoting CNS metastasis in Non-Small Cell Lung Cancer

MUC5AC在促进非小细胞肺癌中枢神经系统转移中的作用

• 批准号: 10618916
• 负责人: Apar Kishor Ganti
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618916
• 关键词: Accounting; Animal Model; Antibodies; Applications Grants; Biological Markers; Biology; Brain; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Adhesion; Cell Line; Cessation of life; Clinical; Data; Development; Disease; Epidermal Growth Factor Receptor; Focal Adhesion Kinase 1; Genes; Genetic Engineering; Genetically Engineered Mouse; Goals; In Vitro; Integrin beta4; KRASG12D; Knock-out; Knockout Mice; Knowledge; Lung Neoplasms; MUC5AC gene; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Mediating; Metastatic Neoplasm to the Central Nervous System; Metastatic Neoplasm to the Lung; Metastatic malignant neoplasm to brain; Methods; Modeling; Molecular; Molecular Profiling; Molecular Weight; Morbidity - disease rate; Mucins; Mucous body substance; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenes; Outcome; Outcome Study; Patients; Play; Prognosis; Reporting; Resistance; Role; Sampling; Site; Structure of parenchyma of lung; Survival Rate; Systemic Therapy; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Time; Tumor Cell Migration; Veterans; Woman; brain tissue; cancer cell; cell motility; clinically significant; driver mutation; exosome; experimental study; in vivo; lung cancer cell; lung development; men; mortality; novel marker; novel therapeutics; overexpression; palliative; prevent; tumor progression

Lung Cancer (LC) is the leading cause of cancer-related mortality in the world, accounting for ~24% of cancer- related deaths in both women and men. The predicted 5-year survival rate of non-small-cell lung cancer (NSCLC) is 21%. The high mortality rate of LC patients is attributed to the fact that they usually present at an advanced stage where treatment options are mostly palliative. Brain metastasis remains a major cause of morbidity and mortality in lung cancer. Approximately, 25-40% of NSCLC develop central nervous system (CNS) metastasis. Our recent studies have found that MUC5AC is overexpressed in NSCLC and is associated with poor prognosis. Further, Muc5ac is found to be overexpressed in lung tissues of a genetically engineered mouse model (GEMM) (KrasG12D; AdCre and KrasG12D; Trp53R172H/+; AdCre). We have shown that MUC5AC interacts with integrin β4 and leads to lung cancer cell metastasis by activating focal adhesion kinase (FAK). In addition, we observed that MUC5AC expression is increased in brain metastatic tissues of LC. Based on these studies, we hypothesize that MUC5AC is overexpressed in lung cancer and plays a central role in brain metastasis. To test this hypothesis, we propose three specific aims: Aim 1 will define the role of MUC5AC as a biomarker of brain metastasis and establish its clinicopathological significance in lung cancer brain metastases. In Aim 2, we will systemically delineate the molecular mechanisms of MUC5AC on the development of LC brain metastases. It will highlight the mechanistic and functional significance of MUC5AC/integrin β4 axis in cellular adhesion, progression and metastasis of LC and will identify the presence of MUC5AC in exosomes and its role in metastasis. Finally, Aim 3 will identify the biology of MUC5AC mediated brain metastasis and impact of MUC5AC inhibition, using GEMM models. In this aim, we will use our GEM model and decipher the molecular signature and progression and metastasis of lung tumors in the presence and absence of Muc5ac. We will also isolate tumoroid or exosomes from lung cancer patients and GEMM model, including Muc5ac-/- mice to identify metastatic efficiency. We will use MUC5AC targeting antibodies to determine the effects of MUC5AC inhibition on brain metastases, with the goal of developing potential therapeutic options targeted towards brain metastases. Overall, the outcomes from the study will help to identify therapeutic strategies for lung cancer brain metastatic patients.

肺癌（LC）是世界上与癌症相关死亡率的主要原因，占癌症的24％ - 男女的相关死亡。预计非小细胞肺癌的5年生存率 （NSCLC）为21％。 LC患者的高死亡率归因于他们通常存在于 治疗选择大多是姑息治疗的高级阶段。脑转移仍然是 肺癌的发病率和死亡率。大约有25-40％的NSCLC发展中枢神经系统 （CNS）转移。我们最近的研究发现，MUC5AC在NSCLC中过表达，并且相关 预后不良。此外，发现MUC5AC在基因工程的肺组织中过表达 鼠标模型（GEMM）（KRASG12D； ADCRE和KRASG12D； TRP53R172H/+; ADCRE）。我们已经证明了MUC5AC 与整联蛋白β4相互作用，并通过激活局灶性粘合剂激酶（FAK）导致肺癌细胞转移。在 此外，我们观察到在LC的脑转移组织中，MUC5AC表达增加。基于这些 研究，我们假设MUC5AC在肺癌中过表达，并且在大脑中起着核心作用 转移。 为了检验这一假设，我们提出了三个具体目标：AIM 1将定义MUC5AC作为生物标志物的作用 脑转移并在肺癌脑转移酶中建立其临床病理学意义。在AIM 2中，我们 将系统地描述MUC5AC在LC脑转移发展中的分子机制。 它将强调MUC5AC/整合素β4轴在细胞粘附中的机械和功能意义， LC的进展和转移，并将确定外泌体中MUC5AC的存在及其在其中的作用 转移。最后，AIM 3将确定MUC5AC介导的脑转移的生物学和MUC5AC的影响 抑制，使用GEMM模型。在此目标中，我们将使用我们的宝石模型并破译分子签名 在存在和不存在MUC5AC的情况下，肺部肿瘤的进展和转移。我们还将隔离 来自肺癌患者和GEMM模型的肿瘤或外泌体，包括MUC5AC - / - 小鼠，以鉴定 转移效率。我们将使用MUC5AC靶向抗体来确定MUC5AC抑制作用 在脑转移方面，目的是开发针对大脑的潜在治疗选择 转移。总体而言，该研究的结果将有助于确定肺癌大脑的治疗策略 转移性患者。