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This study identifies endothelial AMBRA1 protein as a critical regulator of blood vessel function in early-stage melanoma metastasis. Researchers found that melanoma tumors induce loss of AMBRA1 in endothelial cells through TGF-beta signaling, leading to vascular dysfunction characterized by increased cell proliferation, impaired cell adhesion, and reduced immune-supportive capacity. Analysis of 121 early-stage melanoma patients showed that loss of AMBRA1 in tumor-associated blood and lymphatic vessels significantly correlated with metastatic progression, particularly in a previously identified at-risk patient subgroup.
Why it matters
This research could improve risk stratification for early-stage melanoma patients by identifying those at higher risk of metastasis based on endothelial AMBRA1 expression. The findings suggest potential therapeutic targets in the tumor microenvironment that could prevent metastatic spread, addressing a critical clinical need since current biomarkers for predicting melanoma progression are limited.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Validated biomarkers for identifying patients with early-stage melanomas at high risk of metastasis are limited. We have previously shown that loss of Activating Molecule in Beclin-1-Regulated Autophagy (AMBRA1) and loricrin in the epidermal microenvironment is associated with tumour recurrence. Here we show that endothelial AMBRA1 deficiency contributes to vascular dysfunction and melanoma progression. Melanoma-conditioned media or exposure to TGF{beta}1-3 ligands induced post-transcriptional loss of AMBRA1 in endothelial cells. Transcriptomic profiling in both in vitro and human melanoma single-cell RNA sequencing datasets showed activation of cell-cycle and metabolic programmes alongside suppression of endothelial junction, adhesion and immune-supportive pathways in AMBRA1-deficient endothelial cells. Functionally, AMBRA1 loss increased endothelial cell proliferation, accelerated early tubulogenesis, impaired three-dimensional spheroid adhesion, stabilised endothelial-to-mesenchymal transition-associated transcription factors Slug and Snail, and reduced Claudin-5, VE-cadherin and N-cadherin, indicative of endothelial plasticity and dysfunction. Furthermore, loss of AMBRA1 in a subset of intratumoural and peritumoural blood and lymphatic vessels correlated significantly with metastatic progression in a cohort of 121 non-ulcerated primary AJCC stage I/II melanomas classified as AMBLor at-risk. Collectively, these findings position endothelial AMBRA1 as a regulator of vascular plasticity, dysfunction, and immune-supportive endothelial function in early-stage melanomas, and a marker of a permissive microenvironment associated with metastasis.