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

Abstract

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 Lgr5DTR/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.