Abstract
Finding additional functional targets for combination therapy could improve the outcome for melanoma patients. In a spontaneous metastasis xenograft model of human melanoma a shRNA mediated knockdown of L1CAM more than sevenfold reduced the number of lung metastases after the induction of subcutaneous tumors for two human melanoma cell lines (MeWo, MV3). Whole genome expression arrays of the initially L1CAM high MeWo subcutaneous tumors revealed unchanged or downregulated genes involved in epithelial to mesenchymal transition (EMT) except an upregulation of Jagged 1, indicating a compensatory change in Notch signaling especially as Jagged 1 expression showed an increase in MeWo L1CAM metastases and Jagged 1 was expressed in metastases of the initially L1CAM low MV3 cells as well. Expression of 17 genes showed concordant regulation for L1CAM knockdown tumors of both cell lines. The changes in gene expression indicated changes in the EMT network of the melanoma cells and an increase in p53/p21 and p38 activity contributing to the reduced metastatic potential of the L1CAM knockdowns. Taken together, these data make L1CAM a highly interesting therapeutic target to prevent further metastatic spread in melanoma patients.
Highlights
Malignant melanoma is an extremely dangerous disease with high mortality rates due to the aggressive metastatic potential of melanoma cells
The performed in vitro experiments with the MeWo and MV3 lungs. All control (Luc) and L1CAM knockdown cells gave no clear indication how L1CAM influenced the metastatic behavior of the corresponding xenograft tumors in vivo (Fig 1) as both cell lines displayed different changes, e.g. in proliferation, after L1CAM knockdown
Melanoma cells are rather heterogenic in many aspects[22] which might in part explain why the in vitro changes in behavior differed between the two cell lines
Summary
Malignant melanoma is an extremely dangerous disease with high mortality rates due to the aggressive metastatic potential of melanoma cells. The specific roles of these authors are articulated in the ‘author contributions’ section
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