Wang Wenxi, Yang Hua, Passang Tenzin, Li Yiwen, Zhang Hanwen, Jankowski Shayna E, Zeng Fanyuan, Wang Shuhua, Hsu Po-Chih, Li Jian-Ming, Chen Zihan, Lesinski Gregory B, Mendoza Pia R, Li Ying, Giver Cynthia R, Grossniklaus Hans E, Waller Edmund K
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA; Department of Oncology, Xiangya Hospital, Central South University (CSU), Changsha, China; Department of Radiation Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, China.
Department of Ophthalmology, Emory University, Atlanta, GA, USA.
Cancer Lett. 2025 Sep 28;628:217855. doi: 10.1016/j.canlet.2025.217855. Epub 2025 Jun 5.
Uveal melanoma (UVM) is resistant to immune checkpoint therapy and chemotherapy, resulting in high mortality rates, primarily due to liver metastases. While vasoactive intestinal peptide (VIP) signaling has been identified as an immune checkpoint and therapeutic target in pancreatic cancer, its role in melanoma remains unexplored. This study investigated the impact of a novel VIP receptor antagonist, ANT308, on melanoma cell behavior and tumor growth. Using both murine and human UVM/cutaneous melanoma cell lines, we examined the inhibition of VIP receptor signaling and its effects on cell migration and proliferation in vitro. Mechanistically, ANT308 downregulated melanoma cell adhesion molecule (MCAM) and N-cadherin expression at both the RNA and protein levels, as demonstrated by RNA sequencing and Western blot analyses. Knockdown of the VIP receptor VPAC2 in mouse and human melanoma cells produced similar effects on cell migration, proliferation, and MCAM protein expression, further implicating VIP-VPAC2 signaling in tumor progression. In vivo studies revealed that ANT308 treatment decreased MCAM expression in intraocular primary tumors, reduced the number and size of liver metastases following intraocular or subcutaneous melanoma injection, and showed a trend toward reduced tumor volume at the primary tumor site. In conclusion, our findings indicate that VIP receptor signaling promotes liver metastasis in melanoma, and targeting this pathway with VIP receptor antagonists may represent a novel therapeutic strategy for treating metastatic UVM.
葡萄膜黑色素瘤（UVM）对免疫检查点疗法和化疗具有抗性，导致死亡率很高，主要原因是肝转移。虽然血管活性肠肽（VIP）信号通路已被确定为胰腺癌中的一种免疫检查点和治疗靶点，但其在黑色素瘤中的作用仍未得到探索。本研究调查了一种新型VIP受体拮抗剂ANT308对黑色素瘤细胞行为和肿瘤生长的影响。使用小鼠和人类UVM/皮肤黑色素瘤细胞系，我们在体外检测了VIP受体信号传导的抑制及其对细胞迁移和增殖的影响。从机制上讲，如RNA测序和蛋白质印迹分析所示，ANT308在RNA和蛋白质水平上均下调了黑色素瘤细胞粘附分子（MCAM）和N-钙粘蛋白的表达。在小鼠和人类黑色素瘤细胞中敲低VIP受体VPAC2对细胞迁移、增殖和MCAM蛋白表达产生了类似的影响，进一步表明VIP-VPAC2信号通路参与肿瘤进展。体内研究表明，ANT308治疗可降低眼内原发性肿瘤中MCAM的表达，减少眼内或皮下注射黑色素瘤后肝转移的数量和大小，并显示出原发性肿瘤部位肿瘤体积减小的趋势。总之，我们的研究结果表明，VIP受体信号传导促进黑色素瘤的肝转移，用VIP受体拮抗剂靶向该通路可能代表一种治疗转移性UVM的新型治疗策略。
