Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany.
Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany.
J Exp Med. 2020 Oct 5;217(10). doi: 10.1084/jem.20191515.
Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack of animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here, we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances tumor invasion and metastasis in Trp53ΔIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane. Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four CMSs. Trp53ΔIECAktE17K tumor cells are characterized by Notch3 up-regulation, and treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. In CRC patients, NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically up-regulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.
最近，建立了基于转录组的共识分子亚型（CMS）分类的结直肠癌（CRC），这可能最终有助于 CRC 治疗的个体化。然而，缺乏能够忠实地再现不同分子亚型的动物模型，阻碍了分层治疗概念的充分临床前测试。在这里，我们证明在致癌剂氧化偶氮甲烷的刺激下，肠上皮细胞中 AKT 的组成性激活，显著增强了 Trp53ΔIEC 小鼠（Trp53ΔIECAktE17K）中的肿瘤侵袭和转移。基因表达谱分析表明，Trp53ΔIECAktE17K 肿瘤类似于人类间充质结直肠癌亚型（CMS4），这是四种 CMS 中生存率最差的。Trp53ΔIECAktE17K 肿瘤细胞的特征是 Notch3 上调，用 NOTCH3 抑制抗体治疗 Trp53ΔIECAktE17K 小鼠可减少侵袭和转移。在 CRC 患者中，NOTCH3 表达与肿瘤分级以及淋巴结、远处转移的存在呈正相关，并且在 CMS4 肿瘤中特异性地上调。因此，我们建议 NOTCH3 作为 CMS4 晚期 CRC 患者的潜在靶点。
