Plasticity and CXCR4 in colorectal cancer metastasis
Jan Paul Medema
Scientific director and head of Oncode Institute, Department Head LEXOR – Amsterdam UMC
Host: Atanasio Pandiella.
Phenotypic plasticity is crucial for colorectal cancer (CRC) metastasis, yet the mechanisms regulating plasticity remain poorly understood. Using the murine metastatic KPN (KrasG12D/+/Trp53-/-/RosaN1icd/+) model, two distinct cellular states with dynamic interconversion potential were identified, with WNThigh or fetal-like transcriptional profiles, and CXCR4 served as a marker for the WNThigh population. In contrast, non-metastatic CRC models without NOTCH activity (KP and KPN-N1icdKO) exhibited reduced CXCR4 expression and lacked plasticity, residing in a fetal-like state. Intriguingly, KPN models in which CXCR4 was knocked-out, either in vitro or in vivo, lost plasticity, adopted a fetal-like phenotype, and were unable to form metastases, while primary tumor growth, migratory ability, and liver seeding were unaffected. Similarly, inhibition of WNT signaling, induced a fetal transition and blocked metastasis. Our data highlight the essential role of phenotypic plasticity in metastatic progression of CRC and suggest that CXCR4 is critical for cellular state transitions.
