RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations.
RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations.
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DOI：
10.1038/s41598-017-15704-y
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发表时间：
2017-11-10
影响因子：
4.6
通讯作者：
Hoey T
中科院分区：
文献类型：
--
作者：
Fischer MM;Yeung VP;Cattaruzza F;Hussein R;Yen WC;Murriel C;Evans JW;O'Young G;Brunner AL;Wang M;Cain J;Cancilla B;Kapoun A;Hoey T
Wnt通路中的激活突变是结直肠癌（CRC）的特征。R-spondin（RSPO）家族是一组增强Wnt信号传导的分泌蛋白，并且RSPO 2和RSPO 3基因融合已在CRC中报道。我们以前已经表明，Wnt通路阻断剂表现出有效的组合活性与紫杉烷类抑制肿瘤生长。在本文中，我们发现在具有RSPO 3融合的患者来源的异种移植物模型（PDX）和具有常见CRC突变（如APC、β-连环蛋白或RNF 43）的肿瘤中，RSPO 3拮抗作用与基于紫杉醇的化疗协同。在代表超过90%的CRC的这些后一种类型的肿瘤中，RSPO 3由肿瘤微环境中的基质细胞产生，并且活化突变似乎使肿瘤对Wnt-Rspo协同作用敏感。RSPO 3抑制和紫杉烷治疗的组合提供了一种有效靶向大量结直肠癌和其他肠癌患者的致癌WNT信号传导的方法。
Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.
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影响因子：
64.8
作者：
Seshagiri, Somasekar;Stawiski, Eric W.;Durinck, Steffen;Modrusan, Zora;Storm, Elaine E.;Conboy, Caitlin B.;Chaudhuri, Subhra;Guan, Yinghui;Janakiraman, Vasantharajan;Jaiswal, Bijay S.;Guillory, Joseph;Ha, Connie;Dijkgraaf, Gerrit J. P.;Stinson, Jeremy;Gnad, Florian;Huntley, Melanie A.;Degenhardt, Jeremiah D.;Haverty, Peter M.;Bourgon, Richard;Wang, Weiru;Koeppen, Hartmut;Gentleman, Robert;Starr, Timothy K.;Zhang, Zemin;Largaespada, David A.;Wu, Thomas D.;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
64.8
作者：
Buczacki, Simon J. A.;Zecchini, Heather Ireland;Winton, Douglas J.
通讯作者：
Winton, Douglas J.
影响因子：
4.7
作者：
Hirsch, Daniela;Barker, Nick;Gaiser, Timo
通讯作者：
Gaiser, Timo
影响因子：
64.8
作者：
Yan KS;Janda CY;Chang J;Zheng GXY;Larkin KA;Luca VC;Chia LA;Mah AT;Han A;Terry JM;Ootani A;Roelf K;Lee M;Yuan J;Li X;Bolen CR;Wilhelmy J;Davies PS;Ueno H;von Furstenberg RJ;Belgrader P;Ziraldo SB;Ordonez H;Henning SJ;Wong MH;Snyder MP;Weissman IL;Hsueh AJ;Mikkelsen TS;Garcia KC;Kuo CJ
通讯作者：
Kuo CJ
影响因子：
3.5
作者：
Albuquerque, C;Breukel, C;Smits, R
通讯作者：
Smits, R