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: 10454778
• 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/10454778
• 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; Gene Mutation; 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; Metastatic to; 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; base; 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) 是世界上癌症相关死亡的主要原因，约占癌症的 24% 女性和男性的相关死亡。非小细胞肺癌的预测5年生存率 （非小细胞肺癌）为 21%。 LC 患者的高死亡率归因于他们通常就诊 晚期阶段，治疗方案大多是姑息性的。脑转移仍然是导致癌症的主要原因 肺癌的发病率和死亡率。大约 25-40% 的 NSCLC 出现中枢神经系统 （中枢神经系统）转移。我们最近的研究发现 MUC5AC 在 NSCLC 中过度表达，并且与 预后不良。此外，Muc5ac被发现在基因工程小鼠的肺组织中过度表达。 小鼠模型 (GEMM)（KrasG12D；AdCre 和 KrasG12D；Trp53R172H/+；AdCre）。我们已经证明MUC5AC 与整合素β4相互作用，通过激活粘着斑激酶（FAK）导致肺癌细胞转移。在 此外，我们观察到LC脑转移组织中MUC5AC表达增加。基于这些 研究中，我们假设 MUC5AC 在肺癌中过度表达，并在大脑中发挥核心作用 转移。 为了检验这一假设，我们提出了三个具体目标： 目标 1 将定义 MUC5AC 作为生物标志物的作用 脑转移并建立其在肺癌脑转移中的临床病理学意义。在目标 2 中，我们 将系统地描述MUC5AC对LC脑转移发展的分子机制。 它将强调 MUC5AC/整合素 β4 轴在细胞粘附中的机制和功能意义， LC 的进展和转移，并将确定外泌体中 MUC5AC 的存在及其在 转移。最后，目标 3 将确定 MUC5AC 介导的脑转移的生物学以及 MUC5AC 的影响 抑制，使用 GEMM 模型。为了这个目标，我们将使用我们的 GEM 模型并破译分子特征 Muc5ac 存在和不存在时肺部肿瘤的进展和转移。我们也会隔离 来自肺癌患者和 GEMM 模型（包括 Muc5ac-/- 小鼠）的肿瘤样或外泌体来识别 转移效率。我们将使用MUC5AC靶向抗体来确定MUC5AC抑制的效果 脑转移，目标是开发针对脑的潜在治疗方案 转移。总体而言，该研究的结果将有助于确定肺癌脑部的治疗策略 转移患者。