Defining the Role for A Lipid Kinase in the Progression of Pancreatic Cancer

定义脂质激酶在胰腺癌进展中的作用

基本信息

批准号：
8811520
负责人：
Kun Ling
金额：
$ 20.75万
依托单位：
MAYO CLINIC ROCHESTER
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：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811520
关键词：
1-Phosphatidylinositol 3-Kinase Actins Adenocarcinoma Cell Alleles Animals Antineoplastic Agents Basic Science Biogenesis Biological Markers Biology Cancer Etiology Cell Adhesion Cell Line Cells Cessation of life Clinical Coupled Development Diagnostic Disease Drug Targeting Ductal EGF gene Epidermal Growth Factor Receptor Exhibits Focal Adhesions Genetic Engineering Goals Growth Health Hepatocyte Growth Factor Human Human Development In Situ In Vitro Intervention KRAS2 gene Knowledge Lead Lesion Light Link Lipids Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metaplasia Modeling Molecular Mus Mutation Neoplasm Metastasis Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Ductal Carcinoma Pancreatic Intraepithelial Neoplasia Pancreatic duct Pancreatitis Pathway interactions Patient Care Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Phosphatidylinositols Phospholipids Phosphorylation Phosphotransferases Play Protein Isoforms Publishing Receptor Protein-Tyrosine Kinases Role Second Messenger Systems Signal Pathway Signal Transduction Signaling Molecule Solid Staging Stem cells Survival Rate Testing Therapeutic Translating Transplantation cancer diagnosis cancer stem cell cell motility clinical application in vivo innovation loss of function meetings migration mouse model mutant neoplastic novel diagnostics novel therapeutics outcome forecast pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis research study response second messenger stem trafficking trait tumor

项目摘要

DESCRIPTION (provided by applicant): As the fourth most common cause of cancer-related deaths in the US and the eighth worldwide, pancreatic cancer has an extremely poor prognosis with a <6% 5-year survival rate due to its aggressively metastasis. Although abnormally activated K-Ras and EGFR haven been clearly associated with the initiation and progression of pancreatic cancer, the downstream signaling molecules responding to these stimulation to drive the rapid progression of this malignancy are far from fully understood. This limits the development of efficient diagnostic and therapeutic strategies against this deadly disease. Our long-term goal is to understand the molecules and mechanisms that control the initiation and progression of pancreatic cancer. Toward this end, we start from dissecting the role of a specific lipid kinase, type Iγ phosphatidylinositol phosphate kinase (PIPKIγ), in pancreatic cancer development. PIPKIγ generates phosphatidylinositol-4,5-bisphosphate (PI4,5P2), which is not only the substrate of PI 3-Kinase, but also a critical lipid second messenger for cell migration and invasion by regulating actin reorganization, cell adhesion assembly, and vesicular trafficking. Our published and preliminary results suggest that PIPKIγ is an important player downstream of receptor tyrosine kinases such as EGFR and c-Met in the formation of metastatic pancreatic cancer. In the proposed study, we will employ mouse models to test whether PIPKIγ is necessary for the initiation and progression of pancreatic neoplasia spontaneously generated in these animals. To do so, we have generated mice with conditional deletion of PIPKIγi2 (PIPKIγ isoform that can be phosphorylated by receptor tyrosine kinases) concomitant with K-RasG12D expression with or without p53 loss-of-function mutants in the pancreas. We will determine and compare the initiation and progression of acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia (PanIN), and aggressive pancreatic ductal carcinoma in control and PIPKIγ-depleted pancreata obtained from these animals. In particular, we will determine whether PIPKIγ is required for the initiation, maintenance, and/or differentiation of pancreatic tuft cells, the PanIN stem cells. Whether the receptor tyrosine kinase-mediated phosphorylation is critical for PIPKIγ to promote cancer metastasis will also be tested by suppression/re-expression approach using orthotopical transplantation model. Results from these experiments will shed a light on the signaling pathway downstream of receptor tyrosine kinase and K-Ras in the development of pancreatic cancer. Ultimately, we hope to translate this knowledge into new strategies for detecting cells where PI4,5P2 signaling is not appropriately regulated, before they have the opportunity to develop into aggressive metastatic tumors. Furthermore, these studies will provide potent candidates for new biomarkers and cancer drug targets. The outcomes of this project will clearly benefit both basic research and clinical patient care.

描述（申请人提供）：胰腺癌是美国第四大、全球第八大癌症相关死亡原因，由于其侵袭性异常转移，其预后极差，5年生存率<6%。激活的 K-Ras 和 EGFR 与胰腺癌的发生和进展明确相关，但对这些刺激作出反应以驱动这种恶性肿瘤快速进展的下游信号分子还远未完全了解，这限制了其发展。我们的长期目标是了解控制胰腺癌发生和进展的分子和机制，为此，我们从剖析特定脂质激酶类型的作用开始。 Iγ 磷脂酰肌醇磷酸激酶 (PIPKIγ) 在胰腺癌发展过程中产生磷脂酰肌醇 4,5-二磷酸 (PI4,5P2)。 PIPKIγ 不仅是 PI 3-激酶的底物，而且是通过调节肌动蛋白重组、细胞粘附组装和囊泡运输来实现细胞迁移和侵袭的关键脂质第二信使。我们已发表的初步结果表明，PIPKIγ 是 PI 3-激酶下游的重要参与者。 EGFR 和 c-Met 等受体酪氨酸激酶在转移性胰腺癌形成中的作用在拟议的研究中，我们将采用小鼠模型来测试 PIPKIγ 是否对于转移性胰腺癌的发生和进展是必需的。为此，我们在有条件地删除 PIPKIγi2（可被受体酪氨酸激酶磷酸化的 PIPKIγ 亚型）的同时，在有或没有 p53 功能丧失突变体的情况下表达 K-RasG12D。我们将确定并比较胰腺腺泡到导管化生的发生和进展。特别是，我们将确定 PIPKIγ 是否是胰腺簇细胞（PanIN）的启动、维持和/或分化所必需的。受体酪氨酸激酶介导的磷酸化是否对于PIPKIγ促进癌症转移至关重要，也将通过抑制/重新表达方法进行测试。使用原位移植模型，这些实验的结果将揭示胰腺癌发展中受体酪氨酸激酶和 K-Ras 下游的信号通路，最终，我们希望将这些知识转化为检测 PI4、此外，这些研究将为新的生物标志物和癌症药物靶点提供有效的候选者，该项目的结果显然将使基础研究和临床患者受益。关心。