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（由申请人提供）：K-Ras 基因的激活突变是在人类胰腺癌（PC）样本中检测到的最早且最常见的遗传改变，并且与 PC 的基因工程小鼠模型（GEMM）中的进展和转移相关。 ，致癌 K-Ras 驱动胰腺上皮内瘤变（PanIN 病变）的形成，并且其进展为侵袭性 PC。在恶性转化中发挥不同作用的四种效应途径：MAPK途径（丝裂原激活蛋白激酶）、PI3K途径（磷酸肌醇3激酶）、Ral-GDS（Ral鸟嘌呤核苷酸解离刺激剂）和Rac1 GTPase（Ras相关C3肉毒杆菌）在这些效应子中，最不为人所知的是 Rac1 途径，但最近发现该途径。在转化实验中，Rac1 是 Ras 癌基因转化所必需的，并且 Rac1 的激活突变体可以与 MAPK 途径协同引发恶性转化。生长和致瘤性尚不清楚，其与 MAPK 通路合作的机制也尚不清楚。本提案的目的是阐明这些机制。 MAPK 通路联合作用来控制蛋白质的表达/活性，这些蛋白质在整合细胞-细胞和细胞-基质相互作用的信号中发挥着关键作用，尤其是 YAP 蛋白（Yes 相关蛋白 1）。该假设基于表明的初步数据。 Rac1 或 MAPK 途径的抑制会导致 YAP 蛋白的降解，YAP 是一种控制参与增殖的基因的转录辅激活因子。YAP 的稳定性、位置和活性由参与传感细胞的信号通路控制。细胞和细胞-基质相互作用，例如 Ras 驱动的 PC 的 GEMM 中，YAP 是 PanIN 病变的形成及其进展为侵袭性 PC 所必需的。在我们的端粒酶永生化人胰腺导管细胞中，仅过表达 YAP。为了检验我们的中心假设并定义 Rac1 通路在 PC 的启动和进展中的作用及其与 MAPK 通路的配合，我们提出。三个具体目标：目标 1 将阐明 Rac1 转化活性及其与 MAPK 通路的合作机制；目标 2 将评估人类 PC 样本中的 Rac1 活性和 YAP 水平并评估其病理生物学意义； Rac1 和 MAPK 通路在 GEMM 中 PC 的启动和进展中的合作和相对贡献总之，拟议的工作将阐明 Ras 驱动的致癌机制。并揭示新的治疗靶点，这些靶点有可能用于治疗胰腺癌和其他 Ras 驱动的恶性肿瘤。