ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells
ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells
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ADAMDEC1 在癌症干细胞中维持新型生长因子信号环路
DOI：
10.1101/531509
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Hale J
中科院分区：
文献类型：
--
作者：
Hale J
胶质母细胞瘤(GBM)是一种致命性脑肿瘤，由于细胞异质性、治疗抵抗和高度浸润性而导致预后不良。这些特征优先与GBM癌症干细胞(GSCs)有关，但GSCs如何保持其干性尚不完全清楚，也是密集研究的主题。在这里，我们识别了一个新的信号环，它诱导和维持GSCs。该环由一个非典型的金属蛋白酶、一个去整合素和金属蛋白酶结构域样蛋白Decysin 1(ADAMDEC1)组成，由GSC分泌。ADAMDEC1能迅速溶解成纤维细胞生长因子-2(FGF2)，刺激GSC上表达的成纤维细胞生长因子受体1(FGFR1)。这个信号轴诱导锌指E盒结合同源异型盒1(ZEB1)上调，从而调节ADAMDEC1的表达，形成一个正反馈循环。基因或药物靶向的这个轴的组成部分减弱自我更新和肿瘤生长。这些发现揭示了维持GSC的新信号轴，并强调ADAMDEC1和FGFR1是GBM的潜在治疗靶点。肿瘤干细胞(CSC)在包括胶质母细胞瘤在内的许多癌症中推动肿瘤生长。我们鉴定了一种新的脱落酶，一种去整合素和金属蛋白酶结构域样蛋白Decysin 1，它启动了成纤维细胞生长因子自分泌环路，促进了CSCs的干性。这个环路可以靶向减少胶质母细胞瘤的生长。
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 (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.
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影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
影响因子：
23.9
作者：
Lathia, Justin D.;Heddleston, John M.;Venere, Monica;Rich, Jeremy N.
通讯作者：
Rich, Jeremy N.
影响因子：
15.9
作者：
Wolpert, Fabian;Tritschler, Isabel;Eisele, Guenter
通讯作者：
Eisele, Guenter
影响因子：
11.1
作者：
Siebzehnrubl, Florian A.;Silver, Daniel J.;Tugertimur, Bugra;Deleyrolle, Loic P.;Siebzehnrubl, Dorit;Sarkisian, Matthew R.;Devers, Kelly G.;Yachnis, Antony T.;Kupper, Marius D.;Neal, Daniel;Nabilsi, Nancy H.;Kladde, Michael P.;Suslov, Oleg;Brabletz, Simone;Brabletz, Thomas;Reynolds, Brent A.;Steindler, Dennis A.
通讯作者：
Steindler, Dennis A.
影响因子：
11.1
作者：
Xie Y;Bergström T;Jiang Y;Johansson P;Marinescu VD;Lindberg N;Segerman A;Wicher G;Niklasson M;Baskaran S;Sreedharan S;Everlien I;Kastemar M;Hermansson A;Elfineh L;Libard S;Holland EC;Hesselager G;Alafuzoff I;Westermark B;Nelander S;Forsberg-Nilsson K;Uhrbom L
通讯作者：
Uhrbom L