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: 9883472
• 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/9883472
• 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; 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; 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 development; men; mortality; novel marker; novel therapeutics; outcome forecast; 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的死亡的主要原因，约占癌症死亡的24%。 女性和男性的相关死亡。非小细胞肺癌的5年生存率预测 (NSCLC)为21%。LC患者的高死亡率归因于他们通常出现在 晚期，治疗选择大多是姑息性的。脑转移瘤仍然是 肺癌的发病率和死亡率。大约25%-40%的非小细胞肺癌发展为中枢神经系统 (中枢神经系统)转移。我们最近的研究发现，MUC5AC在非小细胞肺癌中过表达，并与 预后不良。此外，还发现Muc5ac在基因工程动物的肺组织中过表达。 小鼠模型(GEMM)(KrasG12D；AdCre和KrasG12D；Trp53R172H/+；AdCre)。我们已经证明了MUC5AC 与整合素β4相互作用，通过激活粘着斑激酶而导致肺癌细胞的转移。在……里面 此外，我们还观察到MUC5AC在LC脑转移组织中的表达增加。基于这些 研究表明，我们假设MUC5AC在肺癌中过度表达，并在脑中发挥中心作用 转移。 为了验证这一假设，我们提出了三个具体目标：目标1将MUC5AC定义为 探讨肺癌脑转移的临床病理意义。在目标2中，我们 将系统阐述MUC5AC在LC脑转移发生中的分子机制。 它将突出MUC5AC/整合素β4轴在细胞黏附中的机制和功能意义， LC的进展和转移，并将确定MUC5AC在外切体中的存在及其在LC中的作用 转移。最后，目标3将确定MUC5AC介导的脑转移的生物学和MUC5AC的影响 抑制作用，使用GEMM模型。在这个目标中，我们将使用我们的GEM模型并破译分子签名 在Muc5ac存在和不存在的情况下，肺癌的进展和转移。我们还将隔离 肺癌患者肿瘤样体和GEMM模型，包括Muc5ac-/-小鼠的鉴定 转移效率。我们将使用MUC5AC靶向抗体来确定MUC5AC抑制的效果 关于脑转移，目标是开发针对脑转移的潜在治疗方案 转移瘤。总体而言，研究结果将有助于确定肺癌脑的治疗策略 转移性病人。