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（由适用提供）：作为美国与癌症相关死亡的第四个最常见原因，胰腺癌的预后非常差，由于其积极的转移，其5年生存率<6％。尽管绝对活化的K-RAS和EGFR避风港显然与胰腺癌的主动性和进展相关，但响应这些刺激以推动这种恶性肿瘤的快速发展的下游信号分子远未充分理解。这限制了针对这种致命疾病的有效诊断和治疗策略的发展。我们的长期目标是了解控制胰腺癌的主动性和进展的分子和机制。为此，我们从剖析特异性脂质激酶，I型磷脂酰肌醇磷酸激酶（PIPKIγ）在胰腺癌发育中的作用。 PIPKIγ产生磷脂酰肌醇-4,5-双磷酸（PI4,5P2），它不仅是PI 3-激酶的底物，而且是通过调节肌动蛋白重组的细胞迁移和侵袭的关键脂质第二信使，细胞粘合剂组装，细胞粘合剂组装，以及囊泡量。我们发表的初步结果表明，PIPKIγ是受体酪氨酸激酶（例如EGFR和C-MET）下游的重要参与者，如转移性胰腺癌的形成。在拟议的研究中，我们将采用小鼠模型来测试PIPKIγ是否需要在这些动物中赞助的胰腺肿瘤的主动性和进展。为此，我们已经产生了PIPKIγI2的条件缺失（PIPKIγ同工型，可以被受体酪氨酸激酶塑料化）与K-RASG12D表达相关的，具有或没有p53的胰腺功能丧失突变体。我们将确定和比较腺泡到导管化生的主动性和进展，胰腺内肿瘤（PANIN）和对照中的胰腺导管癌在对照和PIPKIγ消耗的胰腺中从这些动物中获得。特别是，我们将确定PIPKIγ是否需要主动，维持和/或分化胰腺簇细胞，Panin干细胞。使用原位移植模型，通过抑制/重新表达方法测试受体酪氨酸激酶介导的磷酸化对PIPKIγ促进癌症转移至关重要。这些实验的结果将阐明受体酪氨酸激酶下游的信号通路和K-RAS在胰腺癌的发展中。最终，我们希望将这些知识转化为检测PI4,5P2信号传导的细胞的新策略，然后才有机会发展为侵袭性转移性肿瘤。此外，这些研究将为新的生物标志物和癌症药物靶标提供潜在的候选者。该项目的结果显然会受益于基础研究和临床患者护理。