# Effect of Age-Dependent Loss of HAPLN1 on Vascular Integrity and Melanoma Metastasis

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2022 · $42,506

## Abstract

The survival rate for metastatic melanoma is only 23%. Melanoma patients over 55 years old have higher
incidence of metastasis than younger patients, independent of other clinical prognostic factors. Our lab has
shown that age-dependent changes in the tumor microenvironment are sufficient to drive this disparity. In
particular, loss of a secreted extracellular matrix protein called HAPLN1 in the aged dermis confers increased
metastasis. HAPLN1 loss coincides with matrix breakdown, which we have shown is sufficient to decrease the
barrier function of lymphatic vessels. However, we do not know whether these changes impact the barrier
function of blood vessels, and how this affects intravasation and metastasis of melanoma cells via this route. My
preliminary studies show that aged mice grow melanoma tumors with significantly more blood vessels compared
to young mice. In addition, these vessels have significantly decreased expression of VE-cadherin, which is an
endothelial cell junctional protein critical for maintaining vascular integrity. However, treating aged mice with
recombinant HAPLN1 is sufficient to rescue these phenotypes. Expression of VE-cadherin is regulated by
positive adhesion receptor/extracellular matrix ligand interactions. Accordingly, we have identified two
endothelial adhesion receptors which are downregulated in the context of aged ECM and whose expression is
dependent on the presence of HAPLN1. Interestingly, we have also shown that aged mice lose the collagen
surrounding their blood vessels, which normally functions to support vascular integrity and act as an adhesion
ligand. Finally, we have shown that endothelial barrier function in vitro is maintained by presence of HAPLN1 in
their substrate matrix. I hypothesize that the ECM structural deficiencies caused by age-dependent loss of
HAPLN1 compromise vascular integrity via aberrant adhesion receptor/ECM interactions and increase
hematogenous intravasation. To investigate this hypothesis, I will carry out the following aims. Aim 1: Identify
the mechanism by which HAPLN1 loss reduces blood vessel integrity. I will determine whether
receptor/ligand interactions are required to modulate VE-cadherin expression in a HAPLN1-dependent manner
via proximal ligation assay and immunofluorescent microscopy. I will also analyze the effect of HAPLN1 on
vascular integrity using an in vitro microfluidics platform. Aim 2: Determine the impact of HAPLN1 on
melanoma cell intravasation in vitro and in vivo. I will assess the contribution of HAPLN1 to in vitro
intravasation of melanoma cells using an “upside down” intravasation assay. I will assess HAPLN1’s role in in
vivo intravasation via vascular imaging. Finally, I will analyze associations between HAPLN1, VE-cadherin, and
angiogenesis, and their relationship to age and outcome in human melanoma biopsies. This study will determine
the mechanism by which dermal extracellular matrix structure contributes to age-related melanoma progression,
whic...

## Key facts

- **NIH application ID:** 10386136
- **Project number:** 1F31CA261065-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Gloria Elizabeth Marino
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,506
- **Award type:** 1
- **Project period:** 2022-02-01 → 2022-12-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386136

## Citation

> US National Institutes of Health, RePORTER application 10386136, Effect of Age-Dependent Loss of HAPLN1 on Vascular Integrity and Melanoma Metastasis (1F31CA261065-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10386136. Licensed CC0.

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