YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition.
YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition.
复制标题
YAP 1介导胃腺癌腹膜转移，其通过YAP 1抑制而减弱。
DOI：
10.1136/gutjnl-2019-319748
复制
发表时间：
2021-01
期刊：
影响因子：
24.5
通讯作者：
Song, Shumei
中科院分区：
文献类型：
--
作者：
Ajani, Jaffer A.;Xu, Yan;Huo, Longfei;Wang, Ruiping;Li, Yuan;Wang, Ying;Pizzi, Melissa Pool;Scott, Ailing;Harada, Kazuto;Ma, Lang;Yao, Xiaodan;Jin, Jiankang;Zhao, Wei;Dong, Xiaochuan;Badgwell, Brian D.;Shanbhag, Namita;Tatlonghari, Ghia;Estrella, Jeannelyn Santiano;Roy-Chowdhuri, Sinchita;Kobayashi, Makoto;Vykoukal, Jody V.;Hanash, Samir M.;Calin, George Adrian;Peng, Guang;Lee, Ju-Seog;Johnson, Randy L.;Wang, Zhenning;Wang, Linghua;Song, Shumei
腹膜癌病(PC；恶性腹水或植入物)发生在大约45%的进展期胃腺癌(GAC)患者中，且与低生存率相关。导致PC的分子事件尚不清楚。YAP1癌基因已经出现在许多肿瘤类型中，但其在PC中的临床意义尚不清楚。在这里，我们研究了YAP1在PC中的作用及其作为治疗靶点的潜力。采用患者来源的PC细胞、患者来源的异种移植(PDX)和原位移植(PDO)模型，在体内外研究YAP1的功能。用免疫荧光和免疫组织化学染色、RNA测序(RNA-Seq)和单细胞RNA-Seq(sc-RNA-Seq)分析YAP1的表达和PC细胞的异质性。用LentiCRISPR/Cas9敲除YAP1和YAP1抑制剂分析其在PC转移中的作用。YAP1在PC肿瘤细胞中高度上调，赋予CSC特性，似乎是转移的驱动因素。YAP1/EpCAM和sc-RNA-Seq双重染色显示PC瘤细胞高度异质性，YAP1高PC细胞具有CSC样特性，在小鼠体内容易形成PDX/PDO肿瘤，但也形成PC，而基因敲除YAP1显著减缓肿瘤生长并消除PDO模型中的PC。此外，YAP1的药物抑制特异性地减少了CSC样特性，并抑制了YAP1高PC细胞中的肿瘤生长，特别是与细胞毒药物联合使用时，尤其是在体内PDX模型中。YAP1对于被YAP1抑制而减弱的PC是必不可少的。我们的数据为临床上针对患有PC的GAC患者靶向YAP1提供了强有力的理论依据。
Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The YAP1 oncogene has emerged in many tumor types, but its clinical significance in PC is unclear. Here we investigated the role of YAP1 in PC and its potential as a therapeutic target. Patient-derived PC cells, patient-derived xenograft (PDX) and orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases. YAP1 was highly upregulated in PC tumor cells, conferred CSC properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumor cells were highly heterogeneous, YAP1high PC cells had CSC-like properties, and easily formed PDX/PDO tumors but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumor growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumor growth in YAP1 high PC cells especially in combination with cytotoxics the in vivo PDX model. YAP1 is essential for PC that is attenuated by YAP1 Inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
登录
查看更多内容
影响因子：
21.3
作者：
Er EE;Valiente M;Ganesh K;Zou Y;Agrawal S;Hu J;Griscom B;Rosenblum M;Boire A;Brogi E;Giancotti FG;Schachner M;Malladi S;Massagué J
通讯作者：
Massagué J
影响因子：
30.8
作者：
Keren-Paz A;Emmanuel R;Samuels Y
通讯作者：
Samuels Y
河马效应子YAP促进了对RAF和MEK靶向的癌症疗法的耐药性。
影响因子：
30.8
作者：
Lin L;Sabnis AJ;Chan E;Olivas V;Cade L;Pazarentzos E;Asthana S;Neel D;Yan JJ;Lu X;Pham L;Wang MM;Karachaliou N;Cao MG;Manzano JL;Ramirez JL;Torres JM;Buttitta F;Rudin CM;Collisson EA;Algazi A;Robinson E;Osman I;Muñoz-Couselo E;Cortes J;Frederick DT;Cooper ZA;McMahon M;Marchetti A;Rosell R;Flaherty KT;Wargo JA;Bivona TG
通讯作者：
Bivona TG
DOI：
10.1158/1078-0432.ccr-14-2191
发表时间：
2015-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Song S;Honjo S;Jin J;Chang SS;Scott AW;Chen Q;Kalhor N;Correa AM;Hofstetter WL;Albarracin CT;Wu TT;Johnson RL;Hung MC;Ajani JA
通讯作者：
Ajani JA
影响因子：
5.4
作者：
Song, Wenlong;Li, Hao;Yang, Bai
通讯作者：
Yang, Bai