Age-dependent loss of HAPLN1 erodes vascular integrity via indirect upregulation of endothelial ICAM1 in melanoma

Gloria E. Marino-Bravante, Alexis E. Carey, Laura Hüser, Agrani Dixit, Vania Wang, Amanpreet Kaur, Ying Liu, Supeng Ding, Rahel Schnellmann, Sharon Gerecht, Luo Gu, T. S.Karin Eisinger-Mathason, Yash Chhabra, Ashani T. Weeraratna

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)350-363
Number of pages14
JournalNature Aging
Volume4
Issue number3
DOIs
StatePublished - Mar 2024

Keywords

  • Aged
  • Animals
  • Collagen/metabolism
  • Extracellular Matrix Proteins/genetics
  • Humans
  • Intercellular Adhesion Molecule-1/genetics
  • Melanoma/genetics
  • Mice
  • Skin Neoplasms/genetics
  • Up-Regulation

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