title: Novel metastatic models of esophageal adenocarcinoma derived from FLO-1 cells highlight the importance of E-cadherin in cancer metastasis.
abstract: There is currently a paucity of preclinical models available to study the metastatic process in esophageal cancer. Here we report FLO-1, and its isogenic derivative FLO-1LM, as two spontaneously metastatic cell line models of human esophageal adenocarcinoma. We show that FLO-1 has undergone epithelial-mesenchymal transition and metastasizes following subcutaneous injection in mice. FLO-1LM, derived from a FLO-1 liver metastasis, has markedly enhanced proliferative, clonogenic, anti-apoptotic, invasive, immune-tolerant and metastatic potential. Genome-wide RNAseq profiling revealed a significant enrichment of metastasis-related pathways in FLO-1LM cells. Moreover, CDH1, which encodes the adhesion molecule E-cadherin, was the most significantly downregulated gene in FLO-1LM compared to FLO-1. Consistent with this, repression of E-cadherin expression in FLO-1 cells resulted in increased metastatic activity. Importantly, reduced E-cadherin expression is commonly reported in esophageal adenocarcinoma and independently predicts poor patient survival. Collectively, these findings highlight the biological importance of E-cadherin activity in the pathogenesis of metastatic esophageal adenocarcinoma and validate the utility of FLO-1 parental and FLO-1LM cells as preclinical models of metastasis in this disease.
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Liu
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Sanne J M
authors.initials: SJ
authors.lastname: Hoefnagel
authors.affiliation: Gastroesophageal Cancer Program, St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, 2010, Australia.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Fisher
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Kausilia K
authors.initials: KK
authors.lastname: Krishnadath
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
authors.forename: Karen G
authors.initials: KG
authors.lastname: Montgomery
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.|The University of Melbourne Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, 3010, Australia.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Busuttil
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Colebatch
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Read
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
authors.forename: Cuong P
authors.initials: CP
authors.lastname: Duong
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.|University of Melbourne Department of Surgery, St Vincent's Hospital, Fitzroy, Victoria, 3065, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Clemons
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit
keywords: CDH1; E-cadherin; animal models; esophageal cancer; metastasis