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: 9126228
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126228
• 关键词: Anchorage-Independent Growth; Animals; Area; Biological Assay; Cells; Complex; Contact Inhibition; Data; Development; Disease Progression; Dissociation; Ductal Epithelial Cell; Genes; Genetically Engineered Mouse; Growth; Guanine Nucleotides; 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; Modeling; Mutation; Neoplasm Metastasis; Oncogenes; Oncogenic; Pancreas; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Patients; Phosphoinositide Pathway; Phosphotransferases; Play; Property; Proteins; Repression; Role; Signal Pathway; Specimen; Telomerase; Testing; Transcription Coactivator; Tumorigenicity; Work; base; beta-Transducin Repeat-Containing Proteins; cancer therapy; carcinogenesis; elongin B; intercellular communication; intervention effect; mouse model; mutant; new therapeutic target; overexpression; pancreatic cancer cells; prognostic; public health relevance; rac1 GTP-Binding Protein; 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（通过应用提供）：K-RAS基因中的激活突变是人类胰腺癌（PC）试样最早，最常见的遗传改变，并且与进展和转移相关。在PC的基因工程小鼠模型（GEMM）中，致癌K-RAS驱动了胰腺上皮内肿瘤（Panin病变）的形成，并驱动其发展为侵入性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 nuclear dissociation stimulator), and Rac1 GTPase (Ras-related C3 botulinum toxin substrate 1).在这些效果中，最不理解的是Rac1途径。但是，最近已证明该途径对于RAS驱动的PC开发至关重要。在转化测定中，RAS癌基因的转化需要Rac1，Rac1的活化突变体可以与MAPK途径进行协调以引起恶性转化。但是，Rac1促进独立于锚定的生长和肿瘤性的特定机制尚不清楚，因此其与MAPK途径合作的机制也尚不清楚。该提案的目的是阐明这些机制。我们的中心假设是RAC1和MAPK途径共同起作用，以控制蛋白质的表达/活性，这些蛋白质在整合来自细胞细胞和Ell Matrix相互作用的信号中起着关键作用，最著名的是YAP蛋白（YAP相关蛋白1）。该假设基于初步数据，表明抑制Rac1或MAPK途径会导致YAP蛋白的降解。 YAP是一种转录共激活因子，控制基因涉及增殖。 YAP的稳定性，位置和活性由参与敏感性细胞细胞和细胞 - 矩阵相互作用（例如河马和WNT途径）的信号通路控制。在RAS驱动的PC的GEMM中，panin病变的形成及其发展为侵入性PC所必需的YAP。在我们的端粒酶免疫化的人胰腺导管细胞中，仅过表达的YAP足以允许独立于锚固的生长。为了测试我们的中心假设并定义了Rac1途径在PC的主动性和发展中的作用及其与MAPK途径的合作，我们提出了三个具体目标：AIM 1将阐明负责RAC1转变活动的机制及其与MAPK途径的合作； AIM 2将评估人类PC标本中的Rac1活性和YAP水平，并评估其病理学意义； AIM 3将描述Rac1和MAPK Pathways在PC中PC在PC中的合作和相对贡献。总的来说，拟议的工作将阐明由RAS驱动的癌变的机制，并揭示了新型的治疗靶标，可以探索这些靶标，以治疗胰腺癌和其他RAS驱动的恶性肿瘤。