Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer.
Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer.
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Tetraspanin 6是结直肠癌发生的调节因子。
DOI：
10.1073/pnas.2011411118
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发表时间：
2021-09-28
影响因子：
11.1
通讯作者：
Berditchevski F
中科院分区：
文献类型：
--
作者：
Andrijes R;Hejmadi RK;Pugh M;Rajesh S;Novitskaya V;Ibrahim M;Overduin M;Tselepis C;Middleton GW;Győrffy B;Beggs AD;Berditchevski F
Tetraspanin蛋白(Tspan6)是Tetraspanin家族的成员。利用体外和体内实验相结合的方法，我们证明了Tspan6通过减弱基于表皮生长因子受体(EGFR)的信号轴而在结直肠癌(CRC)中发挥肿瘤抑制作用。Tspan6与跨膜型转化生长因子-α和接头蛋白Syntenin-1形成三元复合体，负向调节转化生长因子-α的分泌。Tspan6在结直肠癌中的表达经常降低，这与预后不良有关。重要的是，Tspan6在结直肠癌中的表达与肿瘤分子特征无关，与患者对西妥昔单抗更好的反应有关，西妥昔单抗是一种EGFR靶向治疗。这些结果证实Tspan6是结直肠癌发生的调节因子，也是EGFR靶向治疗的潜在预测生物标记物。早期结直肠癌(CRC)的特征是转录网络的复杂重新连接，导致多个基因表达的变化。在这里，我们证明了在Apcmin/+小鼠中研究较少的Tspan6蛋白的缺失，这是一个公认的癌前结直肠癌模型，导致腺瘤形成和肿瘤大小的增加。我们证明，Tspan6缺失的作用是通过增加与细胞外小泡相关的跨膜型转化生长因子-α(tm转化生长因子-α)的产生而激活依赖于表皮生长因子的信号通路。这一途径受接头蛋白Syntenin-1的调控，Syntenin-1在物理上连接Tspan6和tmTGF-α。支持这一点的是，Tspan6在结直肠癌中的表达经常减少或丢失，这与生存不良有关。此外，对表皮生长因子受体(EGFR)靶向临床试验(CON试验)样本的分析表明，Tspan6在结直肠癌中的表达与患者对使用西妥昔单抗的EGFR靶向治疗的更好反应有关。重要的是，Tspan6阳性的近端结肠肿瘤患者(右侧)和那些有KRAS突变的患者对西妥昔单抗的反应比表达低Tspan6水平的患者更好。这些结果证实Tspan6是结直肠癌发生的调节因子，也是超越RAS途径突变的结直肠癌EGFR靶向治疗的潜在预测标记物。
Tetraspanin protein (Tspan6) is a member of the tetraspanin family. Using a combination of in vitro and in vivo assays, we demonstrate that Tspan6 functions as a tumor suppressor in colorectal cancer (CRC) by attenuating the epidermal growth factor receptor (EGFR)–based signaling axis. Tspan6 forms a tripartite complex with transmembrane form of TGF-α and an adaptor protein syntenin-1 and negatively regulates secretion of TGF-α. The expression of Tspan6 is frequently decreased in CRC, and this correlates with poor survival. Importantly, the expression of Tspan6 in CRC correlated independently of tumor molecular profile with better patient responses to Cetuximab, an EGFR-targeted therapy. These results identify Tspan6 as a regulator of CRC development and a potential predictive biomarker for EGFR-targeted therapies. Early stages of colorectal cancer (CRC) development are characterized by a complex rewiring of transcriptional networks resulting in changes in the expression of multiple genes. Here, we demonstrate that the deletion of a poorly studied tetraspanin protein Tspan6 in Apcmin/+ mice, a well-established model for premalignant CRC, resulted in increased incidence of adenoma formation and tumor size. We demonstrate that the effect of Tspan6 deletion results in the activation of EGF-dependent signaling pathways through increased production of the transmembrane form of TGF-α (tmTGF-α) associated with extracellular vesicles. This pathway is modulated by an adaptor protein syntenin-1, which physically links Tspan6 and tmTGF-α. In support of this, the expression of Tspan6 is frequently decreased or lost in CRC, and this correlates with poor survival. Furthermore, the analysis of samples from the epidermal growth factor receptor (EGFR)–targeting clinical trial (COIN trial) has shown that the expression of Tspan6 in CRC correlated with better patient responses to EGFR-targeted therapy involving Cetuximab. Importantly, Tspan6-positive patients with tumors in the proximal colon (right-sided) and those with KRAS mutations had a better response to Cetuximab than the patients that expressed low Tspan6 levels. These results identify Tspan6 as a regulator of CRC development and a potential predictive marker for EGFR-targeted therapies in CRC beyond RAS pathway mutations.
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影响因子：
15.1
作者：
Guix FX;Sannerud R;Berditchevski F;Arranz AM;Horré K;Snellinx A;Thathiah A;Saido T;Saito T;Rajesh S;Overduin M;Kumar-Singh S;Radaelli E;Corthout N;Colombelli J;Tosi S;Munck S;Salas IH;Annaert W;De Strooper B
通讯作者：
De Strooper B
影响因子：
11.2
作者：
Greco, Celine;Bralet, Marie-Pierre;Boucheix, Claude
通讯作者：
Boucheix, Claude
影响因子：
3.9
作者：
Latifkar A;Cerione RA;Antonyak MA
通讯作者：
Antonyak MA
肿瘤相关髓系细胞中的表皮生长因子受体促进小鼠结直肠癌的发展，并与患者的预后相关。
影响因子：
29.4
作者：
Srivatsa S;Paul MC;Cardone C;Holcmann M;Amberg N;Pathria P;Diamanti MA;Linder M;Timelthaler G;Dienes HP;Kenner L;Wrba F;Prager GW;Rose-John S;Eferl R;Liguori G;Botti G;Martinelli E;Greten FR;Ciardiello F;Sibilia M
通讯作者：
Sibilia M
DOI：
10.1073/pnas.1922447117
发表时间：
2020-03-17
影响因子：
11.1
作者：
Ghossoub, Rania;Chery, Marion;Zimmermann, Pascale
通讯作者：
Zimmermann, Pascale