Pancreatic Cancer Metastasis

胰腺癌转移

• 批准号: 10203861
• 负责人: Surinder K. Batra
• 金额: $ 164.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203861
• 关键词: Actins; Animal Model; Animals; Autopsy; Bioinformatics; Biological; Biological Models; Biological Process; Biology; C-terminal; CA-125 Antigen; CRISPR/Cas technology; Cancer Biology; Cell Communication; Cell-Cell Adhesion; Chemosensitization; Clinical; Collaborations; Complex; Databases; Detection; Diagnosis; Diffuse; Disease; Distant; Drug resistance; Early Detection Research Network; Extracellular Matrix; Gene Expression Regulation; Genes; Goals; Growth Factor; Growth Factor Receptors; Histology; Integrin Binding; Integrins; Investigational Therapies; Knock-out; Ligands; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane; Metabolic; Metabolism; Molecular; Mucins; Mutate; Mutation; Neoplasm Metastasis; Oncogenic; PTK2 gene; Pancreas; Pathway interactions; Patients; Process; Prognosis; Program Research Project Grants; Property; Protein Isoforms; Receptor Signaling; Recording of previous events; Research Personnel; Resource Sharing; Role; STAT3 gene; Signal Pathway; Signal Transduction; Site; Specimen; Statistical Data Interpretation; Structure; Testing; The Cancer Genome Atlas; Therapeutic; Tissue Banks; Tissues; Transgenic Mice; animal tissue; anticancer research; autocrine; base; c-myc Genes; cancer cell; cell motility; epithelial to mesenchymal transition; experience; extracellular; glucose uptake; glycosylation; in vivo; ineffective therapies; mutant; neoplastic cell; novel; overexpression; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; paracrine; programs; treatment strategy; tumor; tumor progression

ABSTRACT The overall goal of this P01 proposal is to define the mechanistic role of MUC16 in facilitating pancreatic cancer (PC) metastasis. It is well known pancreatic cancer is one of the lethal cancers and also a diffuse metastatic disease with approximately 45% to 55% of patients diagnosed after the cancer has spread. The molecular mechanisms of metastasis are poorly understood. In cancer cells depolarized mucin expression contributes to altered cell-cell adhesion, aberrant potentiation of growth factor receptor signaling, epithelial-to- mesenchymal transition, and drug resistance. In our recent study we have observed that MUC16/CA125 is a membrane bound mucin, and we have observed its aberrant overexpression during PC progression while no expression was observed in the normal pancreas. Similarly our collaborative study demonstrates that the prognosis of patients with MUC16 cytoplasmic expression was significantly poorer in pancreatic cancer patients. Based on these studies and our preliminary results our general hypothesis for the program project is that MUC16-Cter-mediated signaling, biological effects resulting from mutations of MUC16, and MUC16- induced metabolic reprograming contribute to PC metastasis. To test this hypothesis we are proposing three highly integrated projects investigating the mechanisms by which a multi-domain, muti-functional mucin MUC16 promotes metastasis. First project will focus on the role and mechanism(s) of MUC16 and its C- terminal domain in the metastatic progression of PC. Project 1 will be led by Batra, who has 26 years of experience in the field of pancreatic cancer and mucin biology. Second project will explore the roles of mutated forms of membrane bound and circulating MUC16 and its glycosylation in PC metastasis. This project will be led by Hollingsworth, who has 27 years of experience in the field of pancreatic cancer and mucin biology. Third project will focus on MUC16-mediated metabolic reprograming that induces PC metastasis. This project will be led by Singh, who has 14 years of experience in the field of pancreatic cancer biology. The projects are supported by two scientific cores to facilitate animal studies (Core B), evaluate therapeutic strategies and support clinical and animal tissue collection and analysis (Core C). Additionally, an Administrative and Bioinformatics Core (A) is proposed to integrate the different projects, cores and investigators, provide a coordinated management structure and bioinformatics and statistical data analysis. Overall this P01 program builds on the ongoing strengths in pancreatic cancer research that exist at UNMC and has resulted from a long and productive history of collaboration of participating investigators. We hope to define novel mechanisms of MUC16 mediated PC metastasis which will pave a way for better management of this lethal disease.

摘要