Age-Related Loss of Protein HAPLN1 May Contribute to Metastasis in Melanoma

By: Amy MacDonald, MS
Posted: Tuesday, April 23, 2024

Ashani Weeraratna, PhD, of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues have discovered that age-related reduction in the secreted extracellular matrix protein, HAPLN1, may lead to development of favorable conditions for metastatic processes in melanoma. Specifically, their data, published in the journal, Nature Aging, link HAPLN1-promoted matrix stiffness to an increase in vascular leakage and the possibility of tumor angiogenesis. The researchers hope their preclinical discoveries inform future treatment strategies to block the metastatic process and promote survival in older patients with melanoma.

“As we age, the stiffness of our skin changes,” Dr. Weeraratna explained in a Johns Hopkins press release. “That not only has physical implications, but it also has signaling implications and can lead to increases in new blood vessel growth or disruption of blood vessel function,” she continued.

It is known that age-related disparity in distal metastasis exists in melanoma, with older patients much more likely to present with and progress to metastatic disease. The researchers sought to understand whether there was a connection between this phenomenon and their previously described observation that HAPLN1, which is integral to fibroblast signaling and vascular formation, decreases with age. They conducted an extensive series of in vitro and in vivo murine experiments (including second-harmonic generation imaging, impedance-based assays, and immunocompetent syngeneic mouse studies) to characterize how microenvironmental extracellular matrix changes attributable to HAPLN1 may affect the blood vasculature. They determined that decreases in HAPLN1 led to increased endothelial expression of ICAM1, promoting tumor vascularization. In an important proof of concept, they further demonstrated that blocking ICAM1 (in vivo) reduced both tumor size and metastasis in older mice.

Disclosure: For full disclosures of the study authors, visit nature.com.

Nature Aging

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