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ADAMDEC1 Maintains a Growth Factor Signaling Loop in Cancer Stem Cells
Cardiff Univ, European Canc Stem Cell Res Inst, Sch Biosci, Cardiff, S Glam, Wales.
Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA; Case Comprehens Canc Ctr, Cleveland, OH USA.
Cardiff Univ, European Canc Stem Cell Res Inst, Sch Biosci, Cardiff, S Glam, Wales.
Cardiff Univ, European Canc Stem Cell Res Inst, Sch Biosci, Cardiff, S Glam, Wales.ORCID iD: 0000-0001-6943-9730
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2019 (English)In: Cancer Discovery, ISSN 2159-8274, E-ISSN 2159-8290, Vol. 9, no 11, p. 1574-1589Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 9, no 11, p. 1574-1589
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Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-397633DOI: 10.1158/2159-8290.CD-18-1308ISI: 000494360500026PubMedID: 31434712OAI: oai:DiVA.org:uu-397633DiVA, id: diva2:1372255
Available from: 2019-11-22 Created: 2019-11-22 Last updated: 2019-11-22Bibliographically approved

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Holmberg, Karl O.Forsberg Nilsson, Karin

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