Co-targeting Deregulated WNT and MAPK Signaling Pathways Limits Phenotypic Reprogramming of Intestinal Stem Cell Progeny in KRAS-Hyperactivated Colorectal Cancer

In their recent paper, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer (CRC) growth is driven by a reprogramming of Lrg5+ intestinal stem cells progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related intestinal stem cell and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insight into genomic patterns of CRC and targeted therapy strategies.