Identifying Therapeutic Targets for Stage III Melanoma

在肿瘤进展过程中，黑色素瘤细胞必须离开表皮形成皮肤肿瘤， 招募淋巴管，然后迁移到淋巴结，然后转移到远处的器官。 黑色素瘤的预后与肿瘤深度和淋巴结转移直接相关。因此，理想 早期黑色素瘤的治疗药物不仅可以阻止黑色素瘤的侵袭，而且还可以 防止肿瘤细胞进入淋巴管。我们小组发表的作品确定了 RhoJ是一种允许黑色素瘤细胞抵抗BRAF癌基因诱导的应激的基因，在 转移到淋巴结的黑色素瘤。RhoJ缺失阻碍了Braf突变体的生长 并在体内抑制BRAF突变型痣的形成。除了它的选择性作用之外 在控制BRAF突变黑素细胞生长的过程中，RhoJ在肿瘤血管生成中起着特殊的作用。 瘤周内皮细胞中的RhoJ信号诱导它们产生血管，作为血管的管道 无论是营养物质进入肿瘤还是转移细胞退出肿瘤。近期尚未出版的作品 提示RhoJ缺失抑制淋巴管内皮细胞在周围形成血管的能力 肿瘤。此外，抑制RhoJ信号的小分子似乎不仅阻止了 黑色素瘤体内生长，也阻断了血管内皮细胞生成血管供给肿瘤的能力 体外培养的细胞。在这里，我们认为RhoJ在肿瘤生物学中具有双重作用-它在黑素细胞内作用于 促进肿瘤的形成和内皮细胞内淋巴管的形成 皮肤肿瘤周围的血管，以及远处器官肿瘤周围的血管。我们使用一种 结合最先进的单细胞基因组学、活体成像、新的药理学药物和 转基因小鼠模型：1)确定RhoJ如何作用于黑素细胞以促进早期黑素细胞的生长 肿瘤分期；2)确定RhoJ是否作用于淋巴管内皮细胞以控制肿瘤 淋巴管生成；3)评估RhoJ对肿瘤生长和 活体和人体肿瘤3D模型中的淋巴管生成/血管生成。完成这些研究 将定义一种新的治疗策略，通过同时针对这两种肿瘤来阻止癌症的进展 细胞和供养它们的血管。

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 Recent yet unpublished work suggested that RhoJ deletion inhibited the ability of lymphatic endothelial cells to form vessels around tumors.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.