AKT Function in Pancreatic Tumor Cell Invasiveness and In Vivo Pathogenesis.

AKT 在胰腺肿瘤细胞侵袭和体内发病机制中的功能。

基本信息

批准号：
7769857
负责人：
Deborah A Altomare
金额：
$ 20.86万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7769857
关键词：
AKT Signaling Pathway AKT1 gene AKT2 gene AKT3 gene Affect Apoptosis Breast Breast Cancer Cell Cancer Biology Carcinoma Cell Proliferation Cell physiology Classification Dependence Development Disease Ductal Event Exhibits Funding Mechanisms Future Genetic Goals Histologic Human Investigation KRAS2 gene Laboratories Lead Lesion Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Maps Molecular Molecular Abnormality Molecular Profiling Molecular Target Mus Mutation Neoplasm Metastasis Normal tissue morphology Oncogene Proteins Oncogenic Other Genetics Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic carcinoma Pathogenesis Pathway interactions Peripheral Phosphotransferases Prevention therapy Protein Isoforms Proteins Proto-Oncogene Proteins c-akt Recurrence Refractory Regulation Reporting Resistance Role Signaling Protein Staging Substrate Specificity Tetracyclines Therapeutic Time Transgenic Mice Translating Work cancer prevention carcinogenesis conventional therapy glucose metabolism improved in vivo inhibitor/antagonist insight migration mouse model neoplastic cell novel overexpression pancreatic neoplasm pancreatic tumorigenesis promoter public health relevance response tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is an aggressive and deadly disease that is characterized by invasive, metastatic progression and profound resistance to conventional therapeutics. One central player in hallmark pathways important for tumor growth and progression is the AKT kinase. Studies in this laboratory have highlighted differences between AKT1 and AKT2 with regard to their involvement in human cancer and their expression in normal tissues. One important conclusion from recent AKT isoform studies is that AKT1 and AKT2 may have distinct roles in controlling migration and invasion, at least in breast epithelial and carcinoma cells. However, the regulation of different responses by AKT isoforms is largely unknown and may be context dependent. In this proposal, we will establish how responses to different AKT isoforms translate to pancreatic cancer progression. The central hypothesis of this proposal is that AKT cooperates with genetic perturbations mapped within the classical pancreatic tumor progression cascade to facilitate tumor cell proliferation and survival, but that different AKT isoforms may have different roles in regulating pancreatic tumor cell migration and invasiveness. The study of specific AKT isoforms ultimately may elucidate how to suppress tumor progression without adversely affecting other essential cell functions. The specific aims of this proposal are to: 1) Characterize pancreatic-specific transgenic mice with activated Akt for the development of pancreatic lesions and/or potential to cooperate with activated KrasG12D to accelerate pancreatic malignancy and metastasis. The Pdx1 promoter will be utilized to drive tetracycline-regulatable, constitutively active myristoylated (Myr) Akt1 or Akt2. Mice expressing MyrAkt1 will be crossed with Pdx1-Cre-activated KrasG12D mice to evaluate the potential in vivo cooperation between Kras and Akt oncoproteins. Mice expressing MyrAkt2 will be generated and examined histologically, although crosses to generate MyrAkt2;Pdx1-Cre- activated KrasG12D progeny are expected to be beyond the scope of this proposal. 2) Determine the molecular profile of tumors arising in pancreatic-specific transgenic mice with activated Akt1 and in mice with both activated Akt1 and KrasG12D. We will determine if molecular alterations found in pancreatic tumors from mice expressing MyrAkt1 or MyrAkt1;KrasG12D recapitulate other molecular events important in human pancreatic cancers. Pancreatic tumors also will be examined for recurrent somatic genetic changes that may cooperate oncogenically with activated Akt1. These investigations will enhance our understanding of the role of AKT1 and AKT2 in the molecular pathogenesis of pancreatic cancer and will clarify how different AKT isoforms cooperate with known perturbations in the classical progression pathway to promote pancreatic cancer. The long-range goal, given that AKT is an integral signaling protein in several pathways important for tumor vitality, is to define pathway-specific targets that may lead to improved strategies for pancreatic cancer prevention and/or therapy. PUBLIC HEALTH RELEVANCE: In this proposal, genetically defined mouse models will be used to ascertain whether specific AKT isoforms have different roles in aspects of pancreatic tumor proliferation and/or invasion/metastasis. Tumors arising in these mice will be examined for other molecular alterations that are known to be important for human pancreatic tumor development. These studies are expected to provide insights regarding the pathogenetic implications of AKT perturbations in human pancreatic cancer, and define key molecules in the AKT signaling pathway that may be therapeutically targeted to inhibit refractory or recurrent pancreatic cancer.

描述（由申请人提供）：胰腺导管腺癌是一种侵袭性且致命的疾病，其特征是侵袭性、转移性进展和对常规治疗的严重抵抗。 AKT 激酶是对肿瘤生长和进展很重要的标志性通路中的一个核心参与者。该实验室的研究强调了 AKT1 和 AKT2 在人类癌症的参与及其在正常组织中的表达方面的差异。最近 AKT 同工型研究的一个重要结论是，AKT1 和 AKT2 在控制迁移和侵袭方面可能具有不同的作用，至少在乳腺上皮细胞和癌细胞中是这样。然而，AKT 同工型对不同反应的调节很大程度上未知，并且可能依赖于环境。在本提案中，我们将确定对不同 AKT 同工型的反应如何转化为胰腺癌的进展。该提议的中心假设是 AKT 与经典胰腺肿瘤进展级联中映射的遗传扰动合作，以促进肿瘤细胞增殖和存活，但不同的 AKT 亚型在调节胰腺肿瘤细胞迁移和侵袭方面可能具有不同的作用。对特定 AKT 同工型的研究最终可能会阐明如何抑制肿瘤进展而不会对其他重要细胞功能产生不利影响。该提案的具体目标是：1) 表征具有激活 Akt 的胰腺特异性转基因小鼠的胰腺病变发展和/或与激活的 KrasG12D 合作加速胰腺恶性肿瘤和转移的潜力。 Pdx1 启动子将用于驱动四环素调节的、组成型活性肉豆蔻酰化 (Myr) Akt1 或 Akt2。将表达 MyrAkt1 的小鼠与 Pdx1-Cre 激活的 KrasG12D 小鼠杂交，以评估 Kras 和 Akt 癌蛋白之间潜在的体内合作。将产生表达 MyrAkt2 的小鼠并进行组织学检查，尽管产生 MyrAkt2;Pdx1-Cre 激活的 KrasG12D 后代的杂交预计超出了本提案的范围。 2) 确定具有激活的 Akt1 的胰腺特异性转基因小鼠以及同时具有激活的 Akt1 和 KrasG12D 的小鼠中产生的肿瘤的分子谱。我们将确定在表达 MyrAkt1 或 MyrAkt1;KrasG12D 的小鼠胰腺肿瘤中发现的分子改变是否重现了人类胰腺癌中重要的其他分子事件。还将检查胰腺肿瘤的复发性体细胞遗传变化，这些变化可能与激活的 Akt1 协同致癌。这些研究将增强我们对 AKT1 和 AKT2 在胰腺癌分子发病机制中的作用的理解，并将阐明不同的 AKT 亚型如何与经典进展途径中的已知扰动配合以促进胰腺癌。鉴于 AKT 是对肿瘤活力很重要的多个通路中不可或缺的信号蛋白，长期目标是定义通路特异性靶标，这可能会导致胰腺癌预防和/或治疗策略的改进。公共健康相关性：在本提案中，将使用基因定义的小鼠模型来确定特定的 AKT 亚型在胰腺肿瘤增殖和/或侵袭/转移方面是否具有不同的作用。将检查这些小鼠中产生的肿瘤是否存在已知对人类胰腺肿瘤发展很重要的其他分子改变。这些研究预计将提供有关 AKT 扰动对人类胰腺癌的发病机制影响的见解，并定义 AKT 信号通路中的关键分子，这些分子可在治疗上靶向抑制难治性或复发性胰腺癌。