Abstract A009: Defining and targeting L1CAM-driven metastasis progenitor cells in lung adenocarcinoma

Abstract Metastatic lung adenocarcinoma (LUAD) remains the leading cause of cancer-related mortality worldwide, with metastasis driven by a limited subset of tumor cells. Previous work from our laboratory has demonstrated that these metastasis progenitor cells express the transmembrane glycoprotein L1CAM and exhibit a spectrum of phenotypes reflecting a fetal lung developmental continuum, ranging from early progenitor to more differentiated states. The precise signaling mechanisms underpinning the generation of progenitor cells with heightened metastatic potential have yet to be elucidated. In this study, we reveal that L1CAM orchestrates critical signaling cascades requisite for the initiation and maintenance of metastasis-initiating cells in LUAD. Mechanistically, L1CAM associates with the planar cell polarity (PCP) complex, resulting in activation of the transcription factor c-Jun. Activated c-Jun, as a component of the AP-1 complex, binds to enhancer elements and promotes the establishment of a metastasis-competent progenitor state in concert with the epigenetic regulator CHD1. Therapeutic ablation of these metastatic progenitor cells via a cytotoxic L1CAM-targeting antibody effectively abrogated LUAD metastasis in vivo. Collectively, these findings delineate a novel L1CAM-dependent mechanism that sustains a progenitor cell state essential for metastasis and identifies a promising target for therapeutic intervention. Citation Format: Jin Suk Park, Yasemin Kaygusuz, Carson Kenum1, Lan He, Mohamed I. Gatie, Xueqian Zhuang, Roshan Sharma, Ronan Chaligné, Umesh K. Bhanot, Richard P. Koche, Tuomas Tammela, Anna-Katerina Hadjantonakis, Charles M. Rudin, Joan Massagué. Defining and targeting L1CAM-driven metastasis progenitor cells in lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr A009.