Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization.
Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization.
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DOI：
10.1016/j.devcel.2022.04.010
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发表时间：
2022-05-09
影响因子：
11.8
通讯作者：
Tavazoie, Sohail F.
中科院分区：
文献类型：
--
作者：
Moy, Ryan H.;Nguyen, Alexander;Loo, Jia Min;Yamaguchi, Norihiro;Kajba, Christina M.;Santhanam, Balaji;Ostendorf, Benjamin N.;Wu, Y. Gloria;Tavazoie, Saeed;Tavazoie, Sohail F.
转移性定殖是结直肠癌（CRC）死亡的主要原因。我们采用基因组规模的体内短发夹RNA （shRNA）筛选和验证，鉴定了26个结直肠癌肝脏定植启动子。在这些基因中，我们发现了一个包含多个靶基因的基因簇，包括ITPR3，它促进肝脏转移定植并引发类似的下游基因表达程序。ITPR3是一种对咖啡因敏感的肌醇1,4,5-三磷酸（IP3）受体，通过诱导与非典型NF-κB信号相关的转录因子RELB的表达，从内质网释放钙，并增强转移性定植。遗传学、细胞生物学、药理学和临床关联研究表明，ITPR3和RELB通过促进基底脱落或缺氧暴露时的细胞存活来驱动结直肠癌集落形成。RELB足以驱动ITPR3下游的定殖。我们的研究结果暗示ITPR3/钙/RELB轴在结直肠癌转移集落形成中，并揭示了多种临床病理相关的靶向蛋白是结直肠癌转移定殖的驱动因素。Moy等人通过3型肌醇1,4,5-三磷酸受体ITPR3（一种控制钙从内质网释放的钙通道）和与非典型NF-κB信号相关的转录因子RELB，定义了一种促进结直肠癌细胞存活和肝脏转移的临床相关途径。
Metastatic colonization is the primary cause of death from colorectal cancer (CRC). We employed genome-scale in vivo short hairpin RNA (shRNA) screening and validation to identify 26 promoters of CRC liver colonization. Amongst these genes, we identified a cluster containing multiple targetable genes including ITPR3 that promoted liver metastatic colonization and elicited similar downstream gene expression programs. ITPR3 is a caffeine-sensitive inositol 1,4,5-triphosphate (IP3) receptor that releases calcium from the endoplasmic reticulum and enhanced metastatic colonization by inducing expression of RELB, a transcription factor associated with non-canonical NF-κB signaling. Genetic, cell biological, pharmacologic, and clinical association studies revealed that ITPR3 and RELB drive CRC colony formation by promoting cell survival upon substratum detachment or hypoxic exposure. RELB was sufficient to drive colonization downstream of ITPR3. Our findings implicate the ITPR3/calcium/RELB axis in CRC metastatic colony formation and uncover multiple clinico-pathologically associated targetable proteins as drivers of CRC metastatic colonization. Moy et al. define a clinically relevant pathway that promotes colorectal cancer cell survival and liver metastasis via the type 3 inositol 1,4,5-triphosphate receptor ITPR3, a calcium channel that controls calcium release from the endoplasmic reticulum, and RELB, a transcription factor associated with non-canonical NF-κB signaling.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1126/science.aao3130
发表时间：
2017-10-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Drost J;van Boxtel R;Blokzijl F;Mizutani T;Sasaki N;Sasselli V;de Ligt J;Behjati S;Grolleman JE;van Wezel T;Nik-Zainal S;Kuiper RP;Cuppen E;Clevers H
通讯作者：
Clevers H
影响因子：
24.5
作者：
Guerra, Mateus T.;Florentino, Rodrigo M.;Leite, Maria Fatima
通讯作者：
Leite, Maria Fatima
影响因子：
16
作者：
Goodarzi H;Elemento O;Tavazoie S
通讯作者：
Tavazoie S
影响因子：
11.2
作者：
Kang SS;Han KS;Ku BM;Lee YK;Hong J;Shin HY;Almonte AG;Woo DH;Brat DJ;Hwang EM;Yoo SH;Chung CK;Park SH;Paek SH;Roh EJ;Lee SJ;Park JY;Traynelis SF;Lee CJ
通讯作者：
Lee CJ