Role of L1CAM in retinoblastoma tumorigenesis: identification of novel therapeutic targets Dräger, Oliver Dräger Oliver Metz, Klaus Metz Klaus Busch, Maike Busch Maike Dünker, Nicole Dünker Nicole The study presented focuses on the role of the neuronal cell adhesion molecule L1 cell adhesion molecule (L1CAM) in retinoblastoma (RB), the most common malignant intraocular childhood tumor. L1CAM is differentially expressed in a variety of human cancers and has been suggested as a promising therapeutic target. We likewise observed differential expression patterns for L1CAM in RB cell lines and patient samples. The two proteases involved in ectodomain shedding of L1CAM (L1CAM sheddases: ADAM10 and ADAM17) were likewise differentially expressed in the RB cell lines investigated, and an involvement in L1CAM processing in RB cells could be verified. We also identified ezrin, galectin‐3, and fibroblast growth factor basic as L1CAM signaling target genes in RB cells. Lentiviral<em>L1CAM</em>knockdown induced apoptosis and reduced cell viability, proliferation, growth, and colony formation capacity of RB cells, whereas<em>L1CAM‐</em>overexpressing RB cells displayed the opposite effects. Chicken chorioallantoic membrane assays revealed that<em>L1CAM</em>depletion decreases the tumorigenic and migration potential of RB cells<em>in vivo</em>. Moreover,<em>L1CAM</em>depletion decreased viability and tumor growth of etoposide‐resistant RB cell lines upon etoposide treatment<em>in vitro</em>and<em>in vivo</em>. Thus, L1CAM and its processing sheddases are potential novel targets for future therapeutic RB approaches. 16 4 957-981 957-981 Wiley 2022