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Cancer Discov. 2019 Aug 21. pii: CD-18-1308. doi: 10.1158/2159-8290.CD-18-1308. [Epub ahead of print]

ADAMDEC1 maintains a growth factor signaling loop in cancer stem cells.

Author information

1
European Cancer Stem Cell Research Institute, Cardiff University School of Biosciences.
2
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute.
3
Lerner Research Institute, Cleveland Clinic.
4
CMM, Cleveland Clinic.
5
Cleveland Clinic Lerner College of Medicine.
6
Cardiovascular & Metabolic Sciences, Cleveland Clinic.
7
University of Pavia.
8
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS.
9
Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University.
10
European Cancer Stem Cell Research Institute, Cardiff University School of Biosciences fas@cardiff.ac.uk.

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.

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