Rac1 GTPase in tumorigenesis and progression of pancreatic cancer

Rac1 GTPase 在胰腺癌发生和进展中的作用

• 批准号: 9920108
• 负责人: Surinder K. Batra
• 金额: $ 37.47万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920108
• 关键词: Anchorage-Independent Growth; Animals; Area; Biological Assay; Cells; Complex; Contact Inhibition; Data; Development; Disease Progression; Ductal Epithelial Cell; Genes; Genetically Engineered Mouse; Growth; Guanosine Triphosphate Phosphohydrolases; Human; K-ras Gene; KRAS2 gene; Lesion; Light; Location; MAP Kinase Gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mitogen-Activated Protein Kinases; Mutation; Neoplasm Metastasis; Oncogenes; Oncogenic; Pancreas; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Play; Property; Proteins; Repression; Role; Signal Pathway; Specimen; Telomerase; Testing; Transcription Coactivator; Tumorigenicity; Work; base; beta-Transducin Repeat-Containing Proteins; cancer invasiveness; cancer therapy; carcinogenesis; elongin B; intercellular communication; intervention effect; mutant; new therapeutic target; overexpression; pancreatic cancer cells; pancreatic cancer model; prognostic; public health relevance; rac1 GTP-Binding Protein; ral Guanine Nucleotide Exchange Factor; ras Oncogene; small molecule inhibitor; tumor; tumor growth; tumorigenesis; ubiquitin ligase

 DESCRIPTION (provided by applicant): Activating mutations in the K-Ras gene are the earliest and most common genetic alterations detected in human pancreatic cancer (PC) specimens and are associate with progression and metastasis. In genetically engineered mouse models (GEMMs) of PC, oncogenic K-Ras drives the formation of pancreatic intraepithelial neoplasia (PanIN lesions) and their progression to invasive PC. Oncogenic K-Ras has, at least, four effector pathways that play distinct roles in malignant transformation: MAPK pathway (mitogen-activated protein kinase), PI3K pathway (phosphoinositide 3-kinase), Ral-GDS (Ral guanine nucleotide dissociation stimulator), and Rac1 GTPase (Ras-related C3 botulinum toxin substrate 1). Among these effectors, the least well understood is the Rac1 pathway. Yet, this pathway has recently been shown to be critical for Ras-driven PC development. In transformation assays, Rac1 is required for transformation by the Ras oncogenes, and activated mutants of Rac1 can cooperate with the MAPK pathway to elicit malignant transformation. However, the specific mechanisms by which Rac1 promotes anchorage-independent growth and tumorigenicity are still unclear, so are the mechanisms responsible for its cooperation with the MAPK pathway. The objective of this proposal is to elucidate these mechanisms. Our central hypothesis is that the Rac1 and MAPK pathways act conjointly to control the expression/activity of proteins that play critical roles in integrating signals from cell-cell and ell-matrix interactions, most notably the YAP protein (Yes-associated protein 1). This hypothesis is based on preliminary data indicating that the inhibition of either Rac1 or MAPK pathway causes the degradation of the YAP protein. YAP is a transcriptional co-activator that controls genes involves in proliferation. The stability, location, and activity of YAP is controlled by signaling pathways involved in sensing cell-cell and cell-matrix interactions, such as the Hippo and Wnt pathways. In GEMMs of Ras-driven PC, YAP is required for the formation of PanIN lesions and their progression to invasive PC. In our telomerase-immortalized human pancreatic ductal cells, overexpressed YAP alone is sufficient to allow anchorage-independent growth. To test our central hypothesis and define the role of the Rac1 pathway in the initiation and progression of PC and its cooperation with the MAPK pathway, we propose three Specific Aims: Aim 1 will elucidate the mechanisms responsible for the transforming activity of Rac1 and its cooperation with the MAPK pathway; Aim 2 will evaluate Rac1 activity and YAP levels in human PC specimens and assess their pathobiological significance; and Aim 3 will delineate the cooperation and relative contributions of Rac1 and MAPK pathways in the initiation and progression of PC in GEMMs. Altogether, the proposed work will shed light on the mechanisms underlying Ras-driven carcinogenesis and reveal novel therapeutic targets, which could potentially be exploited for the treatment of pancreatic cancers and other Ras-driven malignancies.

 描述（由申请人提供）：K-RAS基因中的激活突变是Tommon Genetation Incre Atic Cancer（PC）样本，并且与PC的基因工程小鼠Mousels（Gemms）相关。 RAS驱动上皮内肿瘤（Panin病变）及其对侵入性PC的程序，至少是四个在恶性转化中起独特作用的效应途径：MAPK途径（Mapk途径） ）RAL-GDS（RAL鸟嘌呤核苷酸解离刺激剂）和Rac1 GTPase（与Ras相关的C3 IUM毒素底物1）。对于RAS驱动的PC开发，RAS Oncogenes和Rac1的激活MAPK与MAPK的方式合作，Rac1促进了与锚定的生长和肿瘤的特定机制。途径基于初步数据，表明YAP蛋白的抑制作用。河马和WNT途径。 Rac1途径在PC的启动过程中及其与MAPK途径的合作，我们提出了三个特定的目标：AIM 1将阐明负责Rac1和MAPK途径的转换活动的机制； RAC1在PC启动PC中的合作和相对贡献。