Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
Cancer Res. 2017 Apr 1;77(7):1763-1774. doi: 10.1158/0008-5472.CAN-16-2821. Epub 2017 Feb 15.
About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling, which promotes tumor invasion and progression. Here, we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status. Using primary colorectal cancer tissues, xenograft models, and MAPK reporter constructs, we showed that tumor cells with high MAPK activity resided specifically at the leading tumor edge, ceased to proliferate, underwent epithelial-mesenchymal transition (EMT), and expressed markers related to colon cancer stem cells. In KRAS-mutant colon cancer, regulation of MAPK signaling was preserved through remaining wild-type RAS isoforms. Moreover, using a lineage tracing strategy, we provide evidence that high MAPK activity marked a progenitor cell compartment of growth-fueling colon cancer cells Our results imply that differential MAPK signaling balances EMT, cancer stem cell potential, and tumor growth in colorectal cancer. .
大约 40%的结直肠癌存在 KRAS 突变伴下游 MAPK 信号通路的激活，这促进了肿瘤的侵袭和进展。在这里，我们报告称 MAPK 信号通路显示出很强的肿瘤内异质性，出人意料的是，无论 KRAS 突变状态如何，MAPK 信号通路仍受到调控。我们使用原发性结直肠癌组织、异种移植模型和 MAPK 报告基因构建体表明，具有高 MAPK 活性的肿瘤细胞特异性地位于肿瘤前沿，停止增殖，经历上皮-间充质转化（EMT），并表达与结肠癌细胞干相关的标志物。在 KRAS 突变的结肠癌中，MAPK 信号通路的调节通过剩余的野生型 RAS 同工型得以维持。此外，我们使用谱系追踪策略提供了证据表明，高 MAPK 活性标记了促进结肠癌细胞生长的祖细胞区室。我们的结果表明，不同的 MAPK 信号通路平衡了结直肠癌中的 EMT、癌症干细胞潜能和肿瘤生长。
