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

描述（由申请人提供）：胰腺癌是美国第四大、全球第八大最常见的癌症相关死亡原因，由于其转移性强，预后极差，5年生存率<6%。虽然异常激活的K-Ras和EGFR与胰腺癌的发生和发展有明显的联系，但下游信号分子对这些刺激的反应驱动这种恶性肿瘤的快速进展还远未完全了解。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发生和发展的分子和机制。为此，我们从剖析一种特定的脂质激酶，i型γ磷脂酰肌醇磷酸激酶（PIPKIγ）在胰腺癌发展中的作用开始。PIPKIγ产生磷脂酰肌醇-4,5-二磷酸（pi4,5p2），它不仅是PI 3-激酶的底物，而且通过调节肌动蛋白重组、细胞粘附组装和囊泡运输，是细胞迁移和入侵的关键脂质第二信使。我们发表的和初步的研究结果表明，PIPKIγ在转移性胰腺癌的形成过程中是受体酪氨酸激酶（如EGFR和c-Met）下游的一个重要参与者。在拟议的研究中，我们将采用小鼠模型来测试PIPKIγ是否对这些动物自发产生的胰腺肿瘤的发生和进展是必要的。为了做到这一点，我们在胰腺中产生了PIPKIγi2 （PIPKIγ亚型可以被受体酪氨酸激酶磷酸化）条件缺失的小鼠，并伴有K-RasG12D表达，有或没有p53功能丧失突变体。我们将确定并比较对照和从这些动物获得的pipki γ-缺失胰腺中腺泡到导管化生、胰腺上皮内瘤变（PanIN）和侵袭性胰腺导管癌的发生和进展。特别是，我们将确定PIPKIγ是否需要胰腺簇状细胞（PanIN干细胞）的启动、维持和/或分化。受体酪氨酸激酶介导的磷酸化是否对PIPKIγ促进癌症转移至关重要，也将通过原位移植模型的抑制/再表达方法进行测试。这些实验结果将揭示酪氨酸激酶和K-Ras受体下游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，以便在PI4,5P2信号没有得到适当调节的细胞有机会发展为侵袭性转移性肿瘤之前检测它们。此外，这些研究将为新的生物标志物和癌症药物靶点提供强有力的候选物。这个项目的成果显然将有利于基础研究和临床病人护理。

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.