Tcf-Dependent gene products in lymphogenic metastasis

The canonical Wnt pathway induces Tcf-dependent gene expression and is a complex regulator of vascular development during embryogenesis. Increasing evidence suggests that Wnt signals may play a role in vessel formation in the adult organism, specifically in cancer. We wish to explore the role of Wnt signals in melanoma: do they alter lymphogenic metastatic spread to sentinel nodes? This raises questions regarding the functionality of newly formed lymphatic vessels, questions of how lymph-angiogenesis is induced, of how melanoma cells reach the lumen of a lymphatic vessel and how they colonize the lymph node. To analyze these questions, we will use our SCID mouse model engrafted with human melanoma cells. In this model, primary melanoma grows in the skin and metastasizes to the sentinel node in a way reminiscent to the human situation. By transgene expression in melanoma cells this system allows to modify expression of wnt or wnt-dependent genes and to correlate results with altered lymph-angiogenesis and metastasis. Results of this approach will be compared with the situation in human patients by analyzing expression of proteins in tissue arrays of primary tumors and of metastatic lesions. Research aims are (a) to describe the contribution of canonical Wnt signaling to lymphogenic tumor spread (b) to characterize the gene products of the Wnt pathway that mediate these effects and (c) to provide novel tools to delay or even inhibit lymph node metastasis.

The canonical Wnt pathway induces Tcf-dependent gene expression and is a complex regulator of vascular development during embryogenesis. Increasing evidence suggests that Wnt signals may play a role in vessel formation in the adult organism, specifically in cancer. We wish to explore the role of Wnt signals in melanoma: do they alter lymphogenic metastatic spread to sentinel nodes? This raises questions regarding the functionality of newly formed lymphatic vessels, questions of how lymph-angiogenesis is induced, of how melanoma cells reach the lumen of a lymphatic vessel and how they colonize the lymph node. To analyze these questions, we will use our SCID mouse model engrafted with human melanoma cells. In this model, primary melanoma grows in the skin and metastasizes to the sentinel node in a way reminiscent to the human situation. By transgene expression in melanoma cells this system allows to modify expression of wnt or wnt-dependent genes and to correlate results with altered lymph-angiogenesis and metastasis. Results of this approach will be compared with the situation in human patients by analyzing expression of proteins in tissue arrays of primary tumors and of metastatic lesions. Research aims are (a) to describe the contribution of canonical Wnt signaling to lymphogenic tumor spread (b) to characterize the gene products of the Wnt pathway that mediate these effects and (c) to provide novel tools to delay or even inhibit lymph node metastasis.