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bioRxiv · 10.1101/2025.08.22.671773

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

Park, J. S.·Kaygusuz, Y.·Kenum, C.·He, L.·Gatie, M. I.·Zhuang, X.·Sharma, R.·Chaligne, R.·Bhanot, U. K.·Koche, R. P.·Tammela, T.·Hadjantonakis, A.-K.·Rudin, C. M.·Massague, J.
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Abstract

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 SOX2 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.

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Park, J. S., Kaygusuz, Y., Kenum, C., He, L., Gatie, M. I., Zhuang, X., Sharma, R., Chaligne, R., Bhanot, U. K., Koche, R. P., Tammela, T., Hadjantonakis, A.-K., Rudin, C. M., Massague, J.. 2025-08-23. L1CAM signaling through planar cell polarity generates SOX2+ metastatic progenitors in lung adenocarcinoma. https://doi.org/10.1101/2025.08.22.671773

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