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

Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unknown. Here, we elucidate a process that drives the emergence of SOX2 metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells in the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions. L1CAM-mediated adhesion to perivascular basement membrane is known to stimulate the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2+ LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2 LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.