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

• 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
• 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

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癌症相关死亡原因和全球第八大癌症相关死亡原因，由于其侵袭性转移，预后极差，5年生存率为6%。虽然异常激活的K-RAS和EGFR与胰腺癌的发生和发展明显相关，但对这些刺激反应的下游信号分子推动胰腺癌快速发展的机制还远未完全清楚。这限制了针对这种致命疾病的有效诊断和治疗战略的发展。我们的长期目标是了解控制胰腺癌发生和发展的分子和机制。为此，我们首先剖析了一种特殊的脂蛋白激酶--I型磷脂酰肌醇磷酸酶(PIPKIγγ)在胰腺癌发生中的作用。PIPKIγ产生磷脂酰肌醇-4，5-二磷酸(PI4，5P2)，它不仅是PI3-Kinase的底物，而且通过调节肌动蛋白重组、细胞黏附组装和囊泡运输，成为细胞迁移和侵袭的关键脂质第二信使。我们已发表的和初步的结果表明，PIPKIγ在转移性胰腺癌的形成中是受体酪氨酸激酶如EGFR和c-Met下游的重要参与者。在拟议的研究中，我们将使用小鼠模型来测试PIPKIγ是否是这些动物自发产生的胰腺肿瘤的启动和发展所必需的。为此，我们建立了条件缺失PIPKIγi2(可被受体酪氨酸激酶磷酸化的PIPKIγ异构体)伴随K-RasG12D表达的小鼠，并在胰腺中存在或不存在P53功能丧失突变。我们将确定和比较腺泡至导管化生、胰腺上皮内瘤变(Panin)和侵袭性胰腺导管癌在对照组和从这些动物获得的PIPKIγ耗竭胰腺癌中的发生和发展。特别是，我们将确定是否需要PIPKIγ来启动、维持和/或分化胰腺丛状细胞，即胰岛干细胞。受体酪氨酸激酶介导的磷酸化是否在PIPKIγ促进肿瘤转移中起关键作用，还将通过原位移植模型的抑制/再表达方法进行验证。这些实验的结果将阐明受体酪氨酸激酶和K-RAS下游的信号通路在胰腺癌发展中的作用。最终，我们希望将这些知识转化为新的策略，在细胞有机会发展为侵袭性转移肿瘤之前，检测PI4，5P2信号没有得到适当调控的细胞。此外，这些研究将为新的生物标记物和抗癌药物靶点提供有力的候选。该项目的成果显然将使基础研究和临床病人护理都受益。