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Lookup NU author(s): Dr Ioana Cosgarea, Dr Roisin Stout, Dr Katie BestORCiD, Professor Penny LovatORCiD
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The loss of AMBRA1 and Loricrin (AMBLor) in the epidermis overlying nonulcerated early-stage primary melanomas has recently been identified as a prognostic biomarker and is mediated by tumoral secretion of TGFb2 (Ellis et al 2020, Cosgarea et al 2021). Pilot data shows loss of epidermal AMBRA1 overlying primary melanomas is also associated with loss of expression in the surrounding tumor endothelium, suggesting endothelial AMBRA1 expression may define tumors at risk of metastasis. The aim of the present study was to evaluate endothelial AMBRA1 expression as a potential companion biomarker for personalized adjuvant treatment, and to define the mechanisms mediating its loss. Semi-quantitative automated immunohistochemical analysis of AMBRA1 expression in FFPE sections derived from a cohort of 47 non-ulcerated AJCC stage I/II melanomas, with loss of AMBLor in the peri-tumoral epidermis, revealed variable AMBRA1 expression levels in the endothelium of vessel sub-populations within intra- and/or peri-tumoral locations, possibly reflecting tumor and microenvironment heterogeneity. Treatment of human umbilical vein endothelial cells (HUVEC) cultured on an extra-cellular matrix with recombinant TGFb2 resulted in reduced tubule formation and expression of the tight junction protein Claudin5, but no change in AMBRA1 expression. Further investigation of TGFb family ligands revealed treatment of HUVECs with BMP7 for 72 hours resulted in a small reduction in AMBRA1 expression. Collectively these data suggest the reduction of endothelial AMBRA1 and Claudin5 expression contribute to the loss of vascular integrity but are mediated through different ligands of the TGFb superfamily. Endothelial AMBRA1/Claudin5 expression may therefore serve as early biomarkers of metastasis for high-risk early-stage cutaneous melanomas.
Author(s): Cosgarea I, Stout R, Best K, Sloan P, Armstrong J, Lovat P
Publication type: Conference Proceedings (inc. Abstract)
Publication status: Published
Conference Name: 1st International Societies for Investigative Dermatology Meeting (ISID 2023)
Year of Conference: 2023
Pages: S212-S212
Online publication date: 17/04/2023
Acceptance date: 02/04/2018
ISSN: 1523-1747
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/j.jid.2023.03.1249
DOI: 10.1016/j.jid.2023.03.1249
Series Title: Journal of Investigative Dermatology
