Endothelial AMBRA1 loss contributes to vascular dysregulation facilitating metastatic progression in early-stage melanoma
- 1John Dawson Drug Discovery and Development Research Institute, University of Sunderland
Abstract
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.
Related
- ACAN regulates VSMC mitochondrial homeostasis through the YAP1/TAZ pathway and contributes to the onset and progression of aortic dissection
- Neutrophil-derived oncostatin m contributes to endothelial cell dysfunction during Treponema denticola interaction
- Endothelial Redox Dysregulation in Pulmonary Arterial Hypertension: Compartmentalized Mechanisms and Therapeutic Implications
- The VCPIP1‐UBE3A Deubiquitination‐Ubiquitination Cascade Contributes to Castration‐Resistant Prostate Cancer Progression
- Endothelial protein C receptor expression as a marker of reduced metastatic risk in primary melanoma
BibTeX
@misc{walker2026endothelial,
title = {{Endothelial AMBRA1 loss contributes to vascular dysregulation facilitating metastatic progression in early-stage melanoma}},
author = {L. Walker and R. Stout and M. Di Rienzo and K. Best and S. Bisegna and L. Occhigrossi and I. Cosgarea and P. Sloan and G. Richardson and R. Strippoli and M. Piacentini and G. M. Fimia and P. E. Lovat and J. Armstrong},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755318},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755318v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Endothelial AMBRA1 loss contributes to vascular dysregulation facilitating metastatic progression in early-stage melanoma
AU - L. Walker
AU - R. Stout
AU - M. Di Rienzo
AU - K. Best
AU - S. Bisegna
AU - L. Occhigrossi
AU - I. Cosgarea
AU - P. Sloan
AU - G. Richardson
AU - R. Strippoli
AU - M. Piacentini
AU - G. M. Fimia
AU - P. E. Lovat
AU - J. Armstrong
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755318
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755318v1
AB - 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.
ER -