L1 Cell Adhesion Molecule (L1CAM) Promotes Tumorigenicity and Metastatic Potential in Non-Small-Cell Lung Cancer

Running Title: L1CAM in non-small cell lung cancer Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: Non-small-cell lung cancer (NSCLC) is a highly metastatic cancer with limited treatment options, thus requiring development of novel targeted therapies. Our group previously identified L1 cell adhesion molecule (L1CAM) expression as a member of a prognostic multi-gene expression signature for NSCLC patients. However, there is little information on the biological function of L1CAM in lung cancer cells. The present study investigates the functional and prognostic role of L1CAM in NSCLC. Experimental Design: Cox proportional hazards regression analysis was performed on four independent published mRNA expression datasets of primary NSCLCs. L1CAM expression was suppressed by short-hairpin RNA (shRNA)-mediated silencing in human NSCLC cell lines. Effects were assessed by examining in vitro migration and invasion, in vivo tumorigenicity in mice, and metastatic potential using an orthotopic xenograft rat model of lung cancer. Results: L1CAM is an independent prognostic marker in resected NSCLC patients, with overexpression strongly associated with worse prognosis. L1CAM downregulation significantly decreased cell motility and invasiveness in lung cancer cells and reduced tumor formation and growth in mice. Cells with L1CAM downregulation were deficient in constitutive extracellular-signal regulated kinase (Erk) activation. Orthotopic studies showed that L1CAM suppression in highly metastatic lung cancer cells significantly decreases spread to distant organs, including bone and kidney. Conclusion: L1CAM is a novel pro-metastatic gene in NSCLC and its downregulation may effectively suppress NSCLC tumor growth and metastasis. Targeted inhibition of L1CAM may be a novel therapy for NSCLC. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Thirty to sixty percent of early stage non-small cell lung cancer (NSCLC) patients still develop metastatic recurrence after complete surgical resection. Although adjuvant chemotherapy has been shown to modestly increase the survival of these patients, novel targeted therapies are urgently needed to improve adjuvant treatment. This study shows that in NSCLC with high L1CAM expression, tumor growth and systemic metastasis are inhibited by L1CAM downregulation in subcutaneous and orthotopic models, respectively. We also confirm that L1CAM is a prognostic marker for poor NSCLC outcome and plays a significant role in promoting invasiveness and motility of NSCLC cells. The results of our study highlight targeting of L1CAM as a potentially important novel therapy for NSCLC patients. Author manuscripts have been peer reviewed and accepted for …