Cell adhesion molecules have a profound influence on cancer development, effectively promoting or repressing the development of malignant disease. L1 (or L1-CAM) is a neural cell adhesion molecule that is overexpressed in neuroectodermal tumors. In malignant melanoma, L1-expression correlates with the development of metastatic disease. Recent evidence suggests that L1 may promote the vascularization of tumors and facilitate melanoma cell survival and invasion. The objective is to define the role of L1 in melanoma progression. This work will address a significant gap in our knowledge and will determine whether L1 is a suitable target for therapeutic intervention. There are three aims:
AIM #1 : L1 is proposed to result in the activation of signaling pathways that induce a highly motile and invasive phenotype in malignant melanoma. Induction of this phenotype is. further proposed to result from direct co-operation between L1 and integrins.
This aim will test the hypothesis that direct L1-integrin interaction results in the activation of signaling pathways that promote melanoma cell motility, invasion, and gene transcription. Based on preliminary data, emphasis will be placed on interactions with the 'progression related' integrin alphavbeta3 and on the contribution of the mitogen-activated protein kinase (MAPK) pathway.
AIM#2 : Animal studies will directly assess the contribution of L1 to melanoma survival, growth, and metastasis. Metastasis will be evaluated in an experimental pulmonary metastasis model, while tumor cell survival and growth will be assessed in the dermal microenvironment. Further studies will test the hypothesis that L1 can promote metastasis by stabilizing tumor-platelet interactions or by promoting migration across the host vasculature.
AIM #3 : The goal is to demonstrate that L1 cleavage products contribute to the vascularization of malignant melanoma. We have identified two L1 fragments that are released by melanoma cells as a result of Iosttranslational cleavage. These cleavage products will be tested for proangiogenic activity and for their ability to promote tumor vascularization. Proangiogenic mechanisms will be identified.
