Breaking the cycle: How targeting CD44v6/MET signaling disrupts colorectal cancer cell plasticity

The concept of cancer stemness is undergoing rapid evolution, facilitated by technological advances allowing the tracking and elimination of stem cells in vivo . Following their identification in solid tumors, cancer stem cells were placed at the center of tumor initiation, growth and metastasis. However, increasing evidence suggests that stemness is a cellular state that can be acquired by differentiated cells in a process called plasticity. Here we show that CD44v6 may act as a molecular switch controlling plasticity of colorectal cancer cells. CD44v6/MET signaling controls the reappearance of Lgr5 ⁺ cells after ablation, in vitro and in vivo as demonstrated in tumor organoids derived from Lgr5 ^DTR/eGFP mice using a CD44v6 blocking peptide. CD44v6 also affects the YAP/TAZ signaling pathway, involved in the very first steps of plasticity. In view of the essential role of plasticity for the establishment of metastases, blocking CD44v6 signaling may represent a pivotal and promising therapy.