A RAC-GEF network critical for early intestinal tumourigenesis.
A RAC-GEF network critical for early intestinal tumourigenesis.
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DOI：
10.1038/s41467-020-20255-4
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发表时间：
2021-01-04
影响因子：
16.6
通讯作者：
Sansom OJ
中科院分区：
文献类型：
--
作者：
Pickering KA;Gilroy K;Cassidy JW;Fey SK;Najumudeen AK;Zeiger LB;Vincent DF;Gay DM;Johansson J;Fordham RP;Miller B;Clark W;Hedley A;Unal EB;Kiel C;McGhee E;Machesky LM;Nixon C;Johnsson AE;Bain M;Strathdee D;van Hoof SR;Medema JP;Anderson KI;Brachmann SM;Stucke VM;Malliri A;Drysdale M;Turner M;Serrano L;Myant K;Campbell AD;Sansom OJ
Rac1活性是肠道内环境稳定的关键，也是小鼠肠道内肿瘤抑制基因APC缺失所导致的过度增殖所必需的。为了避免直接靶向对动态平衡的影响，我们认为通过RAC-GEF间接靶向RAC1可能是有效的。对APC缺陷的肠道组织进行转录图谱分析，确定Vav3和Tiam1为关键靶点。这些基因的缺失表明，虽然TIAM1缺乏可以抑制APC诱导的过度增殖，但它对肿瘤的发生没有影响，而VAV3缺乏则没有影响。有趣的是，任何一个基因的缺失都会导致Vav2的上调，随后这三个基因(Vav2、−/−、Vav3、−/−、Tiam1、−/−)都被靶向，深刻地抑制了过度增殖、肿瘤发生和Rac1活性，而不影响正常的体内平衡。关键的是，致癌的KRAS突变否定了观察到的RAC-环境基金依赖性。总而言之，这些数据表明，虽然靶向RAC-Global分子可能在早期阶段具有治疗效果，但这种好处可能在晚期疾病中消失。小分子GTP酶RAC1的缺失抑制了APC缺失引起的肠道肿瘤的发生，但影响了正常的肠道内环境平衡。在这里，作者提供了一种通过联合靶向三个RAC-GEF来降低RAC1活性的替代方法，并表明这种方法延缓了肠道肿瘤的发生，而不会对正常的肠道结构产生不利影响。
RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2−/− Vav3−/− Tiam1−/−), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease. Loss of small GTPase RAC1 suppresses intestinal tumorigenesis caused by APC loss, but impacts normal intestinal homeostasis. Here, the authors provide an alternative method of reducing RAC1 activity by the combined targeting of three RAC-GEFs and show that this approach delays intestinal tumorigenesis without the detrimental effects on normal intestinal architecture.
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影响因子：
5.7
作者：
Bid HK;Roberts RD;Manchanda PK;Houghton PJ
通讯作者：
Houghton PJ
影响因子：
15.3
作者：
Fujikawa, K;Miletic, AV;Alt, FW;Faccio, R;Brown, T;Hoog, J;Fredericks, J;Nishi, S;Mildiner, S;Moores, SL;Brugge, J;Rosen, FS;Swat, W
通讯作者：
Swat, W
影响因子：
50.3
作者：
Diamantopoulou Z;White G;Fadlullah MZH;Dreger M;Pickering K;Maltas J;Ashton G;MacLeod R;Baillie GS;Kouskoff V;Lacaud G;Murray GI;Sansom OJ;Hurlstone AFL;Malliri A
通讯作者：
Malliri A
影响因子：
64.5
作者：
GRODEN, J;THLIVERIS, A;WHITE, R
通讯作者：
WHITE, R
影响因子：
--
作者：
Cook, Danielle R;Solski, Patricia A;Der, Channing J
通讯作者：
Der, Channing J