Cardiff University School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff, United Kingdom.
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Cancer Discov. 2019 Nov;9(11):1574-1589. doi: 10.1158/2159-8290.CD-18-1308. Epub 2019 Aug 21.
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..
胶质母细胞瘤（GBM）是一种致命的脑肿瘤，其预后不良归因于细胞异质性、治疗耐药性和高度浸润性。这些特征与 GBM 癌症干细胞（GSC）优先相关，但 GSCs 如何维持其干性仍不完全清楚，这是一个激烈研究的课题。在这里，我们确定了一个新的信号环路，该环路由 GSCs 分泌的非典型金属蛋白酶 ADAMDEC1 诱导和维持。ADAMDEC1 迅速溶解 FGF2 以刺激 GSCs 上表达的 FGFR1。FGFR1 信号通过 ERK1/2 诱导 ZEB1 的上调，通过 miR-203 调节 ADAMDEC1 的表达，从而形成正反馈环。该轴的成分的遗传或药物靶向减弱了自我更新和肿瘤生长。这些发现揭示了 GSC 维持的新信号轴，并强调 ADAMDEC1 和 FGFR1 作为 GBM 的潜在治疗靶点。意义：癌症干细胞（CSC）在包括 GBM 在内的许多癌症中驱动肿瘤生长。我们鉴定了一种新型的解体酶 ADAMDEC1，它启动了 FGF 自分泌环，以促进 CSCs 的干性。可以靶向该环以减少 GBM 生长。
