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0This research article from Nature Genetics explores how the interplay between MAPK and WNT signaling pathways drives colorectal cancer development. While KRAS mutations (MAPK pathway) are typically insufficient to start intestinal tumors, the study demonstrates they induce a plastic, regenerative cell state that suppresses traditional Lgr5+ stem cells. Researchers found that tumor initiation specifically requires WNT pathway activation to establish a stem-like state, whereas MAPK hyperactivation powers subsequent tumor growth. By analyzing mouse models and single-cell data, the authors show that cancer cells transition between these two distinct states to survive. This cellular plasticity and state-shifting may explain why some targeted therapies, such as KRAS inhibitors, are less effective in treating colorectal cancer compared to other malignancies. Ultimately, the findings suggest that successful treatment requires simultaneously targeting both pathways to overcome the tumor's ability to adapt.
References:
Moore A R, Biehs B, Kljavin N, et al. Dynamic transitioning between MAPK-driven and WNT-driven cell states drives intestinal cancer and shapes therapy response[J]. Nature Genetics, 2026: 1-10.
