ADAMDEC1 Maintains a Growth Factor Signaling Loop in Cancer Stem Cells.
ADAM Proteins
/ metabolism
Animals
Brain Neoplasms
/ genetics
Cell Line, Tumor
Feedback, Physiological
Female
Fibroblast Growth Factor 2
/ metabolism
Glioblastoma
/ genetics
Humans
MicroRNAs
/ genetics
Neoplasm Transplantation
Neoplastic Stem Cells
/ metabolism
Receptor, Fibroblast Growth Factor, Type 1
/ metabolism
Signal Transduction
Zinc Finger E-box-Binding Homeobox 1
/ metabolism
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
09
11
2018
revised:
02
07
2019
accepted:
07
08
2019
pubmed:
23
8
2019
medline:
22
8
2020
entrez:
23
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31434712
pii: 2159-8290.CD-18-1308
doi: 10.1158/2159-8290.CD-18-1308
pmc: PMC7400732
mid: NIHMS1609589
doi:
Substances chimiques
MIRN203 microRNA, human
0
MicroRNAs
0
ZEB1 protein, human
0
Zinc Finger E-box-Binding Homeobox 1
0
Fibroblast Growth Factor 2
103107-01-3
FGFR1 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 1
EC 2.7.10.1
ADAM Proteins
EC 3.4.24.-
decysin
EC 3.4.24.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1574-1589Subventions
Organisme : Medical Research Council
ID : MR/S007709/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL130090
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA059366
Pays : United States
Organisme : Cancer Research UK
Pays : United Kingdom
Informations de copyright
©2019 American Association for Cancer Research.
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