Defining the role of ERK1 and ERK2 in Pancreatic Cancer

定义 ERK1 和 ERK2 在胰腺癌中的作用

• 批准号: 8835707
• 负责人: Meagan B Ryan
• 金额: $ 3.35万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-04 至 2018-02-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835707
• 关键词: Accounting; Adenocarcinoma Cell; Adhesions; Agar; Anchorage-Independent Growth; Apoptosis; Automobile Driving; BRAF gene; Biological Assay; Biological Process; Cancer Biology; Cancer Etiology; Cell Cycle Arrest; Cell Cycle Regulation; Cell Line; Cell physiology; Cells; Cessation of life; Dependency; Development; Disease; Docking; Doxycycline; E-Cadherin; Ectopic Expression; Embryo; Employee Strikes; Epithelial; Event; Fellowship; Flow Cytometry; Foundations; Genes; Genetic; Genetically Engineered Mouse; Glycolysis; Goals; Growth; Immunofluorescence Immunologic; KRAS2 gene; Knockout Mice; Lead; Left; Literature; MAPK1 gene; MAPK3 gene; MEKs; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Melanoma Cell; Mesenchymal; Metabolic; Migration Assay; Mitogen-Activated Protein Kinases; Mutate; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peptides; Phosphorylation; Phosphotransferases; Play; Ploidies; Process; Propidium Diiodide; Protein Isoforms; Protein Kinase; Proteins; Ras/Raf; Reporting; Research; Research Personnel; Research Technics; Role; STAT1 gene; Sampling; Series; Signal Transduction; Site; Staining method; Stains; Survival Rate; Testing; Therapeutic Intervention; Tumor Cell Invasion; United States; Vimentin; Western Blotting; annexin A5; anticancer research; base; c-myc Genes; cell behavior; cell motility; epithelial to mesenchymal transition; genetic regulatory protein; knock-down; knowledge base; malignant breast neoplasm; migration; mouse model; mutant; novel; outcome forecast; public health relevance; research study; senescence; skills; small hairpin RNA; standard care; therapeutic target; transcription factor; tumor

 DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with a poor prognosis and limited treatment options. Pancreatic ductal adenocarcinoma (PDAC) accounts for the greatest number of these cases. The gene KRAS is mutated in greater than 95% of PDAC cases, and this leads to the activation of the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) pathway. Substantial experimental evidence implicates the key role of this protein kinase cascade in driving KRAS-dependent PDAC growth. Despite this importance, the mechanisms by which ERK drives PDAC growth remain surprisingly unresolved. At every level of the Ras-Raf-MEK-ERK cascade there are structurally and functionally related isoforms. There is now strong evidence for striking differences in the role of different Ras and Raf isoforms in signaling and cancer. Whether this is also the case for the two highly related ERK1 and ERK2 isoforms, which share 84% sequence identity, remains underexplored. Much of our current understanding of ERK biological function comes from studies on "ERK1/2" that did not distinguish between these two isoforms. In addition, ERK1/2 are capable of phosphorylating greater than 200 known substrates, but there is little understanding of which of these substrates are important drivers of the ERK/MAPK pathway. The extensive list of substrates causes further complexity for studies regarding which substrates play an active role in the development and maintenance of pancreatic cancer. Based on some reports in the literature suggesting that ERK1 and ERK2 may play different roles in certain circumstances, I performed preliminary studies to determine whether these two isoforms are interchangeable in PDAC. My studies using shRNA directed against ERK1 or ERK2 in a panel of 10 PDAC cell lines showed that loss of ERK1 or ERK2 reduced both anchorage-dependent clonogenic growth and anchorage-independent soft agar growth, indicating that neither of these highly related isoforms can compensate functionally for the loss of the other. Therefore, I hypothesize that ERK1 and ERK2 have distinct and nonredundant roles in driving KRAS-mutant pancreatic cancer growth. I propose three specific aims to test my hypothesis: I will (1) define the dependency of KRAS-mutant PDAC growth on ERK1 and ERK2; (2) define ERK1 and ERK2 roles in PDAC epithelial to mesenchymal transformation, invasion and metabolic alterations; and, (3) Identify ERK isoform-dependent substrates in PDAC. These studies will investigate the divergent and shared functions of ERK1 and ERK2 in pancreatic cancer and have the potential to discover novel signaling mechanisms of this critical node in the ERK MAPK pathway. This fellowship will also enhance my research skills, establish a firm foundation in basic and translational cancer biology and help develop my skills to become an independent investigator in cancer research.