Awardees

Alec K Gramann  |  Ceol Lab  |  Melanoma Research Foundation Medical Student Research Grant

In many types of cancer, less differentiated tumors are more strongly associated with a poor patient prognosis. These tumors tend to be more aggressive: they have higher proliferation rates, a greater propensity for invasion and metastasis, and increased resistance to therapy compared to more differentiated tumors. Less differentiated tumors, by their nature, share characteristics with their embryonic cells of origin. In melanoma, these less differentiated tumors are associated with a neural crest identity that is acquired during early stages of tumor initiation and is present through tumor progression. Previous studies have shown that acquisition of a neural crest identity is a necessary step during initiation of early melanoma lesions and supports fundamental properties of aggressive tumors such as invasion and metastasis. However, the mechanisms of generating a neural crest identity are unknown. Recently, our lab has identified growth differentiation factor 6 (GDF6) as a novel melanoma oncogene. GDF6, a bone morphogenetic protein (BMP) ligand, is recurrently amplified in both human and zebrafish melanomas, and expressed in tumors but not normal melanocytes. We have shown GDF6 acts to prevent differentiation and suppress apoptosis in established melanomas, both in vitro and in vivo. Additionally, we have found that GDF6 regulates expression of multiple neural crest and melanocyte factors previously implicated in melanoma. Upon knockdown of GDF6, we observed downregulation of select neural crest factors coupled with upregulation of melanocyte differentiation factors, leading to melanoma cell differentiation and ultimately cell death. These results suggest that GDF6 plays a role in regulating oncogenic neural crest identity. Here, we look to identify the role of GDF6 and BMP signaling in establishing a neural crest identity during melanoma initiation and explore oncogenic characteristics imparted by GDF6 during melanoma progression. I hypothesize that GDF6-depenent BMP signaling acts to initiate a neural crest identity in melanomas to promote tumor initiation and aggressive tumor characteristics. I further hypothesize that loss of BMP activity leads to differentiation (and in tumors death of differentiating cells), making GDF6 an attractive target for differentiation therapy in melanoma.