Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma

Laura Hüser; Yash Chhabra; Olesia Gololobova; Vania Wang; Guanshu Liu; Agrani Dixit; Murilo Ramos Rocha; Elizabeth I Harper; Mitchell E Fane; Gloria E Marino-Bravante; Daniel J Zabransky; Kathy Q Cai; Jochen Utikal; Barbara S Slusher; Jeremy Walston; Evan J Lipson; Kenneth W Witwer; Ashani T Weeraratna

doi:10.1016/j.celrep.2024.114721

Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma

Cell Rep. 2024 Sep 24;43(9):114721. doi: 10.1016/j.celrep.2024.114721. Epub 2024 Sep 9.

Authors

Laura Hüser¹, Yash Chhabra², Olesia Gololobova³, Vania Wang⁴, Guanshu Liu⁵, Agrani Dixit⁶, Murilo Ramos Rocha⁴, Elizabeth I Harper⁴, Mitchell E Fane², Gloria E Marino-Bravante⁴, Daniel J Zabransky⁴, Kathy Q Cai⁷, Jochen Utikal⁸, Barbara S Slusher⁹, Jeremy Walston¹⁰, Evan J Lipson¹¹, Kenneth W Witwer¹², Ashani T Weeraratna¹³

Affiliations

¹ Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
² Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Research Program Cancer Signaling and Microenvironment, Fox Chase Institute for Cancer Research, Philadelphia, PA, USA.
³ Department of Molecular and Comparative Pathobiology, Johns Hopkins Medicine, Baltimore, MD, USA.
⁴ Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁵ Department of Radiology and Radiological Science, Johns Hopkins Medicine, Baltimore, MD, USA.
⁶ Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Research Program Cancer Signaling and Microenvironment, Fox Chase Institute for Cancer Research, Philadelphia, PA, USA.
⁸ Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
⁹ Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Medicine - Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology - Hematologic Malignancies, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.
¹² Department of Molecular and Comparative Pathobiology, Johns Hopkins Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address: aweeraratna@jhu.edu.

PMID: 39255061
DOI: 10.1016/j.celrep.2024.114721

Abstract

Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.

Keywords: CD9; CP: Cancer; aging; angioepoetin ligand 2 (ANGPTL2); angiogenesis; exosomes; extracellular vesicles; fibroblasts; melanoma.

MeSH terms

Aging / metabolism
Aging / pathology
Angiogenesis
Animals
Cell Line, Tumor
Endothelial Cells / metabolism
Endothelial Cells / pathology
Extracellular Vesicles* / metabolism
Fibroblasts* / metabolism
Fibroblasts* / pathology
Humans
Melanoma* / metabolism
Melanoma* / pathology
Neovascularization, Pathologic* / metabolism
Neovascularization, Pathologic* / pathology
Skin Neoplasms / genetics
Skin Neoplasms / metabolism
Skin Neoplasms / pathology
Tetraspanin 29* / genetics
Tetraspanin 29* / metabolism
Tumor Microenvironment

Substances

Tetraspanin 29
CD9 protein, human

Abstract

MeSH terms

Substances

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