title: Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma.
abstract: Esophageal adenocarcinoma ranks sixth in cancer mortality in the world and its incidence has risen dramatically in the Western population over the last decades. Data presented herein strongly suggest that Notch signaling is critical for esophageal adenocarcinoma and underlies resistance to chemotherapy. We present evidence that Notch signaling drives a cancer stem cell phenotype by regulating genes that establish stemness. Using patient-derived xenograft models, we demonstrate that inhibition of Notch by gamma-secretase inhibitors (GSI) is efficacious in downsizing tumor growth. Moreover, we demonstrate that Notch activity in a patient's ultrasound-assisted endoscopic-derived biopsy might predict outcome to chemotherapy. Therefore, this study provides a proof of concept that inhibition of Notch activity will have efficacy in treating esophageal adenocarcinoma, offering a rationale to lay the foundation for a clinical trial to evaluate the efficacy of GSI in esophageal adenocarcinoma treatment.
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Thiago G
authors.initials: TG
authors.lastname: Da Silva
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Ke
authors.initials: K
authors.lastname: Jin
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Han
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Prathibha
authors.initials: P
authors.lastname: Ranganathan
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Avencia
authors.initials: A
authors.lastname: Sanchez-Mejias
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Dennis Liang
authors.initials: DL
authors.lastname: Fei
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Kelly
authors.initials: K
authors.lastname: Weaver
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Rodrigo Vasquez-Del
authors.initials: RV
authors.lastname: Carpio
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Moscowitz
authors.affiliation: Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Vadim P
authors.initials: VP
authors.lastname: Koshenkov
authors.affiliation: Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Lilly
authors.initials: L
authors.lastname: Sanchez
authors.affiliation: Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Lynne
authors.initials: L
authors.lastname: Sparling
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Xin-Hai
authors.initials: XH
authors.lastname: Pei
authors.affiliation: Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Dido
authors.initials: D
authors.lastname: Franceschi
authors.affiliation: Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Afonso
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
authors.affiliation: Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Livingstone
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. TCapobianco@med.miami.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Capobianco
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases