During the process of tumor progression, melanoma cells must exit the epidermis to form a dermal tumor,
recruit lymphatic vessels, and then migrate to lymph nodes before metastasizing to distant organs.
Melanoma prognosis directly correlates with tumor depth and lymph node metastasis. Therefore, ideal
therapeutic agents for early stage melanoma would not only block melanoma invasion but also
prevent tumor cells from accessing lymphatic vessels. Published work from our group determined that
RhoJ, a gene that allows melanoma cells to resist BRAF oncogene-induced stress, is highly expressed in
melanoma tumors that metastasize to the lymph node. RhoJ deletion stalled the growth of BRAF mutant
melanoma tumors and inhibited the formation of BRAF mutant nevi in vivo. In addition to its selective role
in controlling the growth of BRAF mutant melanocytes, RhoJ plays a specific role in tumor angiogenesis.
RhoJ signaling in peritumoral endothelial cells induces them to generate vessels that serve as conduits for
both nutrients to enter tumors and metastasizing cells to exit tumors. Recent yet unpublished work
suggested that RhoJ deletion inhibited the ability of lymphatic endothelial cells to form vessels around
tumors. Moreover, small molecules that inhibit RhoJ signaling seemed to not only block the growth of
melanoma tumors in vivo, but also blocked the ability of endothelial cells to generate vessels to feed tumor
cells in vitro. Here we propose that RhoJ has a dual role in tumor biology- it acts within the melanocyte to
promote the formation of tumors and within the endothelial cells to promote the formation of lymphatic
vessels around tumors in the skin, and blood vessels around tumors in distant organs. We use a
combination of state of the art single cell genomics, in vivo imaging, novel pharmacologic agents, and
transgenic mouse models to: 1) determine how RhoJ acts in the melanocyte to promote the growth of early
stage tumors; 2) establish whether RhoJ acts in lymphatic endothelial cells to control tumor
lymphangiogenesis; 3) assess the relative contributions of RhoJ to tumor growth and
lymphanigogenesis/angiogenesis in vivo and in 3D models of human tumors. Completion of these studies
will define a new therapeutic strategy that halts cancer progression by simultaneously targeting both tumor
cells and the vessels that feed them.