title: The TALE homeodomain transcription factor MEIS1 activates the pro-metastatic melanoma cell adhesion molecule Mcam to promote migration of pancreatic cancer cells.
abstract: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly types of cancer, and the majority of pancreatic cancer deaths is caused by metastasis. Therapeutic options for systemic disease are limited, in particular due to the heterogeneous events leading to tumor dissemination. Previous studies highlighted an association of the homeodomain transcription factor MEIS1 with a ductal phenotype in pancreatic tissue architecture. Using immunohistochemistry, we demonstrate that MEIS1 is expressed in aberrant duct structures of Ela-TGFα transgenic mice as well as in pancreatic intraepithelial neoplasia (PanINs), primary PDAC, and metastatic disease in Ptf1aCre/+;LSL-KrasG12D/+mice. To assess a putative role of MEIS1 in the progression of PDAC, MEIS1 overexpressing pancreatic cancer cell lines were generated by retroviral gene delivery and assessed for proliferation and migration. MEIS1 did not affect proliferation but increased migration in a subset of cell lines tested. Subsequent genome wide expression analysis identified upregulation of the pro-metastatic gene melanoma cell adhesion molecule (Mcam) in migrating cells. Employing DNA-pulldown and chromatin immunoprecipitation (ChIP) assays we reveal interaction of MEIS1 with the enhancer-DNA of Mcam and its transcriptional activation to facilitate migration of pancreatic cancer cells in vitro. Activation of Mcam through MEIS1 occurs in a cell type dependent fashion, reflecting the different routes that lead to metastasis in vivo. To our knowledge, these results show for the first time a pro-metastatic function of Mcam in pancreatic cancer. © 2016 Wiley Periodicals, Inc.
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|I. Medizinische Klinik, Technische Universität München, Munich, Germany.|II. Medizinische Klinik, Technische Universität München, Munich, Germany.
authors: Johannes
authors: J
authors: von Burstin
authors: II. Medizinische Klinik, Technische Universität München, Munich, Germany.
authors: Friedrich
authors: F
authors: Bachhuber
authors: II. Medizinische Klinik, Technische Universität München, Munich, Germany.
authors: Mariel
authors: M
authors: Paul
authors: II. Medizinische Klinik, Technische Universität München, Munich, Germany.
authors: Roland M
authors: RM
authors: Schmid
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Anil K
authors: AK
authors: Rustgi
mesh_terms: D000818:Animals; D051929:CD146 Antigen / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D051929:CD146 Antigen; D018398:Homeodomain Proteins; C497903:Mcam protein, mouse; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins
keywords: CD146; MEIS1; Mcam; metastasis; pancreatic cancer