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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. and Siebzehnrubl, Florian A. 2019. ADAMDEC1 maintains a growth factor signaling loop in cancer stem cells. Cancer Discovery 9 (11) , pp. 1574-1589. 10.1158/2159-8290.CD-18-1308

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Abstract

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 (GSCs), 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, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. FGFR1 signaling induces upregulation of Zinc-finger E-box-binding homeobox 1 (ZEB1) via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacological 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

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Association for Cancer Research
ISSN: 2159-8274
Date of First Compliant Deposit: 8 August 2019
Date of Acceptance: 7 August 2019
Last Modified: 25 Nov 2020 01:07
URI: http://orca-mwe.cf.ac.uk/id/eprint/124809

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