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

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. This loop consists 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. This signaling axis induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1) that regulates ADAMDEC1 expression, 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. Statement of SignificanceCancer stem cells (CSC) drive tumor growth in many cancers including glioblastoma. We identified a novel sheddase, a disintegrin and metalloproteinase domain-like protein decysin 1, that initiates a fibroblast growth factor autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce glioblastoma growth.

Fibroblast Growth Factor Receptor Functions in Glioblastoma

“…Of note, the stem cell transcription factor ZEB1 regulates N-Cadherin expression, which is associated with EMT and invasion. It is tempting to speculate that N-Cadherin/FGFR1 interactions could constitute a positive feedback loop in GSCs through the activation of ZEB1 and subsequent induction of N-Cadherin and FGFR1 expression [70,72] (see also Section 5.1). NCAMs physically associate with FGFRs and inhibit the high-affinity binding between these receptors and their canonical ligands [56,73].…”

“…This study showed that a targeted expression of PSA-NCAM in C6 glioma cells resulted in increased levels of Olig2, a transcription factor associated with GSCs [75]. While it remains unclear whether this was the result of FGFR transactivation by PSA-NCAM, we have recently shown that OLIG2 can be induced by FGFR1 signaling [72]. Furthermore, the L1-CAM/FGFR1/Anosmin-1 complex regulates neurite branching [76,77,78] and L1-CAM-mediated FGFR1 transactivation induces glioma cell proliferation and motility [79].…”

“…Gene expression analysis of TCGA data (GBM 540) revealed profound heterogeneity of FGFR1–4 expression across GBM patients [72]. Below, we discuss the evidence for the functions of individual FGFRs in glioma.…”

“…FGFR1 expression is regulated by the stem-cell associated transcription factor ZEB1 [70], suggesting that FGFR1 may be associated with GBM cancer stem cells. We recently performed a comprehensive analysis of the functions of FGFR1-3 in GBM and found that FGFR1 indeed is preferentially expressed on GSCs, where it regulates the expression of the critical stem cell transcription factors SOX2, OLIG2, and ZEB1, thereby promoting tumorigenicity in vivo [72]. In summary, FGFR1 is a key regulator of tumor growth, invasion, therapy resistance, and cancer stemness in malignant glioma.…”

“…Our recent analysis of cell-surface FGFR expression patterns in GBM stem cell lines indicates that FGFR2 is nevertheless highly prevalent on GBM cells in vitro [72], but it remains to be tested whether FGFR2 loss results in increased proliferation and/or tumorigenicity. Loss of FGFR2 is associated with a loss of Chr.…”