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ADAMDEC1 Maintains a Growth Factor Signaling Loop in Cancer Stem Cells.
Jimenez-Pascual, Ana; Hale, James S; Kordowski, Anja; Pugh, Jamie; Silver, Daniel J; Bayik, Defne; Roversi, Gustavo; Alban, Tyler J; Rao, Shilpa; Chen, Rui; McIntyre, Thomas M; Colombo, Giorgio; Taraboletti, Giulia; Holmberg, Karl O; Forsberg-Nilsson, Karin; Lathia, Justin D; Siebzehnrubl, Florian A.
Afiliación
  • Jimenez-Pascual A; Cardiff University School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff, United Kingdom.
  • Hale JS; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. fas@cardiff.ac.uk lathiaj@ccf.org james.s.hale@case.edu.
  • Kordowski A; Case Comprehensive Cancer Center, Cleveland, Ohio.
  • Pugh J; Cardiff University School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff, United Kingdom.
  • Silver DJ; Cardiff University School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff, United Kingdom.
  • Bayik D; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • Roversi G; Case Comprehensive Cancer Center, Cleveland, Ohio.
  • Alban TJ; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • Rao S; Case Comprehensive Cancer Center, Cleveland, Ohio.
  • Chen R; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • McIntyre TM; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • Colombo G; Case Comprehensive Cancer Center, Cleveland, Ohio.
  • Taraboletti G; Department of Molecular Medicine, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.
  • Holmberg KO; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • Forsberg-Nilsson K; Case Comprehensive Cancer Center, Cleveland, Ohio.
  • Lathia JD; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • Siebzehnrubl FA; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Cancer Discov ; 9(11): 1574-1589, 2019 11.
Article en En | MEDLINE | ID: mdl-31434712
Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSC), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, ADAMDEC1, secreted by GSCs. ADAMDEC1 rapidly solubilizes FGF2 to stimulate FGFR1 expressed on GSCs. FGFR1 signaling induces upregulation of ZEB1 via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacologic targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. SIGNIFICANCE: Cancer stem cells (CSC) drive tumor growth in many cancers including GBM. We identified a novel sheddase, ADAMDEC1, which initiates an FGF autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce GBM growth.This article is highlighted in the In This Issue feature, p. 1469.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Neoplasias Encefálicas / Transducción de Señal / Glioblastoma / Proteínas ADAM Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Cancer Discov Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Neoplasias Encefálicas / Transducción de Señal / Glioblastoma / Proteínas ADAM Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Cancer Discov Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos