Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan.
Cancer Res. 2018 Mar 1;78(5):1334-1346. doi: 10.1158/0008-5472.CAN-17-3303. Epub 2017 Dec 27.
Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations () in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. mutation caused intestinal adenomas and combination with mutation or deletion induced submucosal invasion. The addition of mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of with and mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that was critical for liver metastasis following splenic transplantation, when this mutation was combined with either plus or deletion, with the highest incidence of metastasis displayed by tumors with a genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upregulated genes in tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFβ signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies. These findings illuminate how key driver mutations in colon cancer cooperate to drive the development of metastatic disease, with potential implications for the development of suitable prevention strategies. .
结直肠癌是由驱动突变的积累所驱动的，但特定突变对恶性进展中不同步骤的贡献尚不完全清楚。在这项研究中，我们在肠上皮细胞中生成了携带不同关键结直肠癌驱动突变组合的小鼠模型，以全面研究它们在原发性肿瘤和转移发展中的作用。 突变导致肠腺瘤，与 突变或 缺失的组合诱导黏膜下浸润。 突变的加入产生了上皮-间充质转化（EMT）样形态和侵袭性肿瘤的淋巴管内侵。相比之下， 与 和 突变的组合不足以进行黏膜下浸润，但仍诱导 EMT 样组织学。使用肿瘤衍生类器官的研究表明， 对于脾脏移植后的肝转移是至关重要的，当这种突变与 加 或 缺失结合时， 基因型的肿瘤显示出最高的转移发生率。肿瘤类器官的 RNA 测序分析定义了具有驱动突变组合特征的不同基因表达谱， 肿瘤中的上调基因与人类转移性结直肠癌标本中的上调基因相似。我们的研究结果表明，在肠上皮细胞中激活 Wnt 和 Kras 并抑制 TGFβ 信号足以促进结直肠癌转移，这可能对开发转移预防策略具有重要意义。这些发现阐明了结直肠癌中关键驱动突变如何合作以促进转移性疾病的发展，这可能对制定合适的预防策略具有潜在意义。
