Oncogenic effects of high MAPK activity in colorectal cancer mark progenitor cells and persist irrespective of RAS mutations
Menée à l'aide de xénogreffes de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, indépendamment de la présence de mutations du gène KRAS, la signalisation MAPK dans différents types cellulaires régule la transition épithélio-mésenchymateuse, la prolifération des cellules souches cancéreuses et la croissance tumorale
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 in vivo. Our results imply that differential MAPK signaling balances EMT, cancer stem cell potential and tumor growth in colorectal cancer.