4838

NODAL

nodal growth differentiation factor;NODAL;nodal growth differentiation factor

nodal homolog

10q22.1

protein-coding

metastatic melanoma continues to be a significantly deadly cancer with a cure rate of < 20% and a median survival of 6 - 9 months. The aggressiveness associated with metastatic melanoma is largely attributable to its inherent plasticity, a property that is mediated by the secretion of Nodal, a stem-cell associated protein belonging to the transforming growth factor-beta superfamily. This is supported by the observations that Nodal expression is limited to invasive vertical growth phase and metastatic melanoma lesions, and that inhibition of Nodal signaling promotes the reversion of metastatic melanoma cells toward a more differentiated, less invasive non-tumorigenic phenotype. Hence, due to its restricted expression pattern and function as a melanoma-tumor-promoter, Nodal (and its signaling partners) present unique targets for both immunologic and pharmacologic therapies.

metastatic melanoma is an aggressive skin cancer associated with poor prognosis. The reactivation of the embryonic morphogen Nodal in metastatic melanoma has previously been shown to regulate the aggressive behavior of these tumor cells. During the establishment of left-right asymmetry in early vertebrate development, Nodal expression is specifically regulated by a Notch signaling pathway. We hypothesize that a similar relationship between Notch and Nodal may be reestablished in melanoma. In this study, we investigate whether cross talk between the Notch and Nodal pathways can explain the reactivation of Nodal in aggressive metastatic melanoma cells. We show a molecular link between Notch and Nodal signaling in the aggressive melanoma cell line MV3 via the activity of an RBPJ-dependent Nodal enhancer element. We show a precise correlation between Notch4 and Nodal expression in multiple aggressive cell lines but not poorly aggressive cell lines. Surprisingly, Notch4 is specifically required for expression of Nodal in aggressive cells and plays a vital role both in the balance of cell growth and in the regulation of the aggressive phenotype. In addition, Notch4 function in vasculogenic mimicry and anchorage-independent growth in vitro is due in part to Notch4 regulation of Nodal. This study identifies an important role for cross talk between Notch4 and Nodal in metastatic melanoma, placing Notch4 upstream of Nodal, and offers a potential molecular target for melanoma therapy.