Abstract 3951: Age-dependent loss of HAPLN1 affects vascular integrity and metastasis in melanoma

Abstract

Abstract Older melanoma patients (>55 years) have worse prognoses than younger patients (<45 years) independent of other clinical prognostic factors. Further, while younger patients have more lymph node metastases, older patients have more distal metastases which significantly impacts their survival. We have shown that age-dependent loss of a secreted factor from dermal fibroblasts, HAPLN1, contributes to increased distal metastasis in vivo via ECM reorganization. Previous work from our lab has shown that age-dependent loss of HAPLN1 confers fewer lymphatic metastases but more lung metastases, consistent with clinical observations. We have demonstrated that this is due to ECM structural degradation and loss of lymphatic vasculature integrity. However, the biological mechanisms by which dermal ECM structure influences metastatic spread and localization are still largely unknown. Here we report that age-dependent loss of HAPLN1 contributes to increased intratumoral neoangiogenesis and decreased vascular integrity. Using immunohistochemistry, we have shown that tumors from aged mice treated with recombinant HAPLN1 have significantly fewer neoangiogenic blood vessels than untreated aged mice, suggesting that HAPLN1 may signal to inhibit neoangiogenesis. Additionally, the intratumoral blood vessels in aged mice treated with recombinant HAPLN1 have increased levels of the adherens junction protein VE-cadherin consistent with levels seen in the tumor vasculature of young mice. Given the pivotal role of intratumoral vasculature in metastasis, we hypothesize that these changes in vessel number and permeability contribute to the increased incidence of lung metastasis in older patients. Further, our data utilizing two-photon microscopy indicate that aged mice have aberrant collagen structure surrounding intratumoral vessels, but that treatment with recombinant HAPLN1 is sufficient to restore a collagen pattern similar to what is seen in young mice. We have additionally demonstrated using an in vitro impedance-based assay that endothelial cell monolayers have a reduced ability to maintain barrier function in the context of ECM without HAPLN1. Given that dermal ECM structural complexity is essential for maintaining vascular integrity, loss of HAPLN1 seems to contribute to this “leaky” vasculature phenotype. In all, these data may provide clues as to why young and aged patients exhibit differential routes of metastases via lymphatic vs. hematogenous dissemination. Citation Format: Gloria E. Marino, Filipe V. Almeida, Ying Liu, Gretchen M. Alicea, Mitchell E. Fane, Ashani T. Weeraratna. Age-dependent loss of HAPLN1 affects vascular integrity and metastasis in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3951.