STEM-07. THE ATYPICAL METALLOPROTEINASE ADAMDEC1 MAINTAINS A NOVEL FGF MEDIATED SIGNALLING NETWORK IN GLIOBLASTOMA CANCER STEM CELLS
STEM-07. THE ATYPICAL METALLOPROTEINASE ADAMDEC1 MAINTAINS A NOVEL FGF MEDIATED SIGNALLING NETWORK IN GLIOBLASTOMA CANCER STEM CELLS
复制标题
STEM-07。
DOI：
10.1093/neuonc/noz175.981
复制
发表时间：
2019
期刊：
影响因子：
15.9
通讯作者：
Jimenez-Pascual A
中科院分区：
文献类型：
--
作者：
Jimenez-Pascual A
胶质母细胞瘤（GBM）是一种致死性脑肿瘤，其不良预后归因于细胞异质性、治疗耐药性和高度浸润性。这些特征优先与GBM癌症干细胞（CSCs）相关，但CSCs如何保持其干性尚不完全清楚，并且是深入研究的主题。干细胞依赖于细胞内在程序和微环境相互作用来调节其维持。最近的研究表明，CSCs可以通过金属蛋白酶的表达来调节其周围的微环境，允许直接修饰提供组织结构完整性的细胞外基质，并通过参与关键细胞表面受体和隔离必需生长因子来指导信号传导。在这里，我们发现了一种新的生长因子信号环，它通过CSCs分泌的非典型金属蛋白酶，一种崩解素和金属蛋白酶结构域样蛋白decysin 1 （ADAMDEC1）诱导和维持CSCs。ADAMDEC1在肿瘤微环境中溶解成纤维细胞生长因子-2 （FGF2）。我们发现CSCs只表达FGF受体1 (FGFR1)， FGFR1与FGF2结合后诱导锌指e盒结合同源盒1 （ZEB1）上调。ZEB1是干细胞和肿瘤起始的调节因子，因此ADAMDEC1-FGF2-FGFR1信号传导促进GBM的恶性。我们进一步表明，ERK磷酸化驱动ZEB1， ZEB1调节ADAMDEC1的表达，通过抑制microRNA-203形成一个正反馈循环。基因或药物靶向这一轴的成分减弱了自我更新和肿瘤生长。这些发现揭示了CSC维持的新信号轴，并强调ADAMDEC1和FGFR1是GBM的潜在治疗靶点。此外，这些发现为GBM的生长提供了一种新的模式，通过这种模式，CSC可以选择性地访问嵌入细胞外基质中的关键生长因子以维持其生长。
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 (CSCs), but how CSCs maintain their stemness is incompletely understood and the subject of intense investigation. CSCs rely both on cell intrinsic programs and microenvironmental interactions to regulate their maintenance. Recent work has demonstrated that CSCs can modulate their surrounding microenvironment by metalloproteinase expression, allowing direct modification of the extracellular matrix that provides structural tissue integrity, and instructive signalling via engagement of key cell surface receptors and sequestration of essential growth factors. Here, we identify a novel growth factor signalling loop that induces and maintains CSCs via an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by CSCs. ADAMDEC1 solubilizes fibroblast growth factor-2 (FGF2) in the tumor microenvironment. We find that CSCs exclusively express FGF receptor 1 (FGFR1), which upon binding of FGF2 induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1). ZEB1 is a regulator of stemness and tumor initiation, and therefore ADAMDEC1-FGF2-FGFR1 signalling promotes malignancy in GBM. We further show that ERK phosphorylation drives ZEB1, which regulates ADAMDEC1 expression, creating a positive feedback loop via repression of microRNA-203. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signalling axis for CSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. In addition, these findings provide a new paradigm for GBM growth through which key growth factors embedded within the extracellular matrix can be selectively accessed by CSC for their maintenance.