Defining oncogenic capacities of PAK7 mutations in human cancer

定义人类癌症中 PAK7 突变的致癌能力

基本信息

批准号：
8879404
负责人：
STEEN HENNING HANSEN
金额：
$ 23.03万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-09 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879404
关键词：
Address Advanced Malignant Neoplasm Affect Apical Apoptosis Architecture Attention Automobile Driving BRAF gene Biological Assay Caco-2 Cells Cadherins Cancer Patient Cancer cell line Carcinoma Cell Line Cell Polarity Cell Proliferation Cell-Cell Adhesion Cells Colon Carcinoma Colorectal Cancer Controlled Study Data Epithelial Epithelial Cells Family Gastric Adenocarcinoma Genes Genome Human MEL Gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Missense Mutation Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Nude Mice Oncogenes Oncogenic Phosphotransferases Probability Property Protein Kinase Relative (related person)Resistance Role STK11 gene Sequence Analysis Staging Technology Testing Therapeutic Tumor Suppressor Proteins Tumorigenicity Work Zinc Fingers anaplastic lymphoma kinase cancer cell cancer genome gastrointestinal carcinoma genome editing genome sequencing improved inhibitor/antagonist insertion/deletion mutation lung Carcinoma matrigel melanoma nuclease oncology p21 activated kinase preclinical study public health relevance research study targeted treatment therapeutic target trait tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Genome sequencing efforts have identified PAK7 (p21-activated kinase 7) as a potentially important cancer kinase. PAK7 ranked 17 among all 518 kinases in probability of harboring driver mutations for human cancer. The vast majority of PAK7 mutations in human cancer are missense and thus suggestive of a role as an oncogene. PAK7 mutations occur in a significant proportion of lung and gastrointestinal carcinomas, as well as in malignant melanomas. Our preliminary data suggest that cancer mutations in PAK7 potently stimulate kinase activity. However, PAK7 is a minimally characterized kinase, thus providing merit to address the following aims: (1) Are putative PAK7 driver mutations required for oncogenic capacities in cancer cells? (2) Are putative PAK7 driver mutations sufficient to promote epithelial oncogenesis? We will rigorously address these aims by genome editing to avoid confounding effects associated with exogenous expression or knockdown of genes. First, we will correct PAK7 missense mutations in human cancer cell lines. We will then determine whether correction of these mutations reverts any transformed capacities that these cell lines possess. Specifically, we will assay cell proliferation, apoptosis, invasion, and tumorigenicity in athymic mice. Second, we will introduce putative PAK7 driver mutations into the relatively well-differentiated colonic Caco-2 cells and bronchial 16HBE14o- cells. In addition to the capacities listed above, we will determine effects of PAK7 cancer mutations on parameters of normal epithelial architecture; a hallmark of differentiated epithelial cells with established tumor suppressor capacities. Specifically, we will test whether naturally occurring PAK7 mutations in cancer affect epithelial cell polarity, cell-cell adhesion, and lumen formation in 3D culture. Collectively, the proposed studies will provide a stringent initial approach to define the oncogenic potential of PAK7 mutations in human cancer and elucidate whether PAK7 represents a promising candidate in expanding targets for cancer therapeutics.

描述（由适用提供）：基因组测序工作已将PAK7（P21激活的激酶7）确定为潜在的重要癌症激酶。 PAK7在所有518种激酶中排名17，这是携带人类癌症驱动器突变的可能性。人类癌症中的绝大多数PAK7突变都是错义的，因此暗示了作为癌基因的作用。 PAK7突变发生在很大一部分的肺和胃肠道癌以及恶性黑色素瘤中。我们的初步数据表明，PAK7中的癌症突变可能刺激激酶活性。但是，PAK7是一种最低特征的激酶，因此提供了以下目的的优点：（1）（1）癌细胞中致癌能力所需的假定PAK7驱动突变？（2）假定的PAK7驱动突变是否足以促进上皮肿瘤发生？我们将通过基因组编辑来严格解决这些目标，以避免与表达性表达或敲低基因相关的混杂作用。首先，我们将纠正人类癌细胞系中的PAK7错义突变。然后，我们将确定这些突变的校正是否会恢复这些细胞系所具有的任何转化能力。具体而言，我们将分析细胞增殖，凋亡，侵袭和肿瘤性。无胸腺小鼠。其次，我们将将推定的PAK7驱动突变引入相对差异化的结肠CACO-2细胞和支气管16HBE14O-细胞。除了上述能力外，我们还将确定PAK7癌症突变对正常上皮结构参数的影响。具有已建立的肿瘤抑制能力的分化上皮细胞的标志。具体而言，我们将测试癌症中天然发生的PAK7突变是否影响3D培养物中的上皮细胞极性，细胞 - 细胞粘合剂和管腔形成。总的来说，拟议的研究将提供一种严格的初始方法来定义人类癌症中PAK7突变的致癌潜力，并阐明PAK7是否代表了扩大癌症治疗靶标的有望候选者。