Melanoma, the most lethal form of skin cancer, often has worse outcomes in older patients. We previously demonstrated that an age-related decrease in the secreted extracellular matrix (ECM) protein HAPLN1 has a role in slowing melanoma progression. Here we show that HAPLN1 in the dermal ECM is sufficient to maintain the integrity of melanoma-associated blood vessels, as indicated by increased collagen and VE-cadherin expression. Specifically, we show that HAPLN1 in the ECM increases hyaluronic acid and decreases endothelial cell expression of ICAM1. ICAM1 phosphorylates and internalizes VE-cadherin, a critical determinant of vascular integrity, resulting in permeable blood vessels. We found that blocking ICAM1 reduces tumor size and metastasis in older mice. These results suggest that HAPLN1 alters endothelial ICAM1expression in an indirect, matrix-dependent manner. Targeting ICAM1 could be a potential treatment strategy for older patients with melanoma, emphasizing the role of aging in tumorigenesis.

黑色素瘤是最致命的皮肤癌，老年患者的预后往往更差。我们之前证明，分泌性细胞外基质 (ECM) 蛋白 HAPLN1 与年龄相关的减少在减缓黑色素瘤进展方面具有作用。在这里，我们发现真皮 ECM 中的 HAPLN1 足以维持黑色素瘤相关血管的完整性，胶原蛋白和 VE-钙粘蛋白表达增加表明了这一点。具体来说，我们发现 ECM 中的 HAPLN1 会增加透明质酸并降低内皮细胞 ICAM1 的表达。 ICAM1 磷酸化并内化 VE-钙粘蛋白（血管完整性的关键决定因素），从而形成可渗透的血管。我们发现阻断 ICAM1 可减少老年小鼠的肿瘤大小和转移。这些结果表明 HAPLN1 以间接、基质依赖性方式改变内皮 ICAM1 表达。靶向 ICAM1 可能是老年黑色素瘤患者的潜在治疗策略，强调了衰老在肿瘤发生中的作用。