L1CAM generates SOX2+ metastatic progenitors through planar cell polarity signaling in lung adenocarcinoma

A primitive SOX2+ progenitor state, rare in primary tumors, becomes prominent in LUAD metastatic lesions and exhibits metastasis-initiating capacity. The signals that determine the emergence of SOX2+ progenitors are unknown.

We report that the cell adhesion molecule L1CAM, a marker of metastasis-initiating regenerative progenitors, plays a crucial role in the emergence of LUAD SOX2+ progenitors. Mechanistically, L1CAM induces the planar cell polarity (PCP) complex to activate c-Jun, which in turn interacts with the chromodomain helicase CHD1 to drive Sox2 transcription and generate metastasis-initiating regenerative progenitors. Treatment with an L1CAM antibody drug conjugate (ADC) effectively eliminates these LUAD cells and eradicates patient-derived xenograft metastases.