TY - JOUR
T1 - Age-dependent loss of HAPLN1 erodes vascular integrity via indirect upregulation of endothelial ICAM1 in melanoma
AU - Marino-Bravante, Gloria E.
AU - Carey, Alexis E.
AU - Hüser, Laura
AU - Dixit, Agrani
AU - Wang, Vania
AU - Kaur, Amanpreet
AU - Liu, Ying
AU - Ding, Supeng
AU - Schnellmann, Rahel
AU - Gerecht, Sharon
AU - Gu, Luo
AU - Eisinger-Mathason, T. S.Karin
AU - Chhabra, Yash
AU - Weeraratna, Ashani T.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85187500527&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85187500527&partnerID=8YFLogxK
U2 - 10.1038/s43587-024-00581-8
DO - 10.1038/s43587-024-00581-8
M3 - Article
C2 - 38472454
AN - SCOPUS:85187500527
SN - 2662-8465
VL - 4
SP - 350
EP - 363
JO - Nature Aging
JF - Nature Aging
IS - 3
ER -