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

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

Johns Hopkins University
German Cancer Research Center

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English
Article number	114721
Journal	Cell Reports
Volume	43
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2024.114721
State	Published - Sep 24 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

aging
angioepoetin ligand 2 (ANGPTL2)
angiogenesis
CD9
CP: Cancer
exosomes
extracellular vesicles
fibroblasts
melanoma
Aging/metabolism
Humans
Tumor Microenvironment
Tetraspanin 29/metabolism
Extracellular Vesicles/metabolism
Melanoma/metabolism
Skin Neoplasms/pathology
Angiogenesis
Endothelial Cells/metabolism
Animals
Fibroblasts/metabolism
Neovascularization, Pathologic/metabolism
Cell Line, Tumor

Access to Document

10.1016/j.celrep.2024.114721

Cite this

Hüser, L., Chhabra, Y., Gololobova, O., Wang, V., Liu, G., Dixit, A., Rocha, M. R., Harper, E. I., Fane, M. E., Marino-Bravante, G. E., Zabransky, D. J., Cai, K. Q., Utikal, J., Slusher, B. S., Walston, J., Lipson, E. J., Witwer, K. W., & Weeraratna, A. T. (2024). Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma. Cell Reports, 43(9), Article 114721. https://doi.org/10.1016/j.celrep.2024.114721

@article{cf7073d124084a4e9b153256b0f9ca71,

title = "Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma",

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 = "aging, angioepoetin ligand 2 (ANGPTL2), angiogenesis, CD9, CP: Cancer, exosomes, extracellular vesicles, fibroblasts, melanoma, Aging/metabolism, Humans, Tumor Microenvironment, Tetraspanin 29/metabolism, Extracellular Vesicles/metabolism, Melanoma/metabolism, Skin Neoplasms/pathology, Angiogenesis, Endothelial Cells/metabolism, Animals, Fibroblasts/metabolism, Neovascularization, Pathologic/metabolism, Cell Line, Tumor",

author = "Laura H{\"u}ser and Yash Chhabra and Olesia Gololobova and Vania Wang and Guanshu Liu and Agrani Dixit and Rocha, \{Murilo Ramos\} and Harper, \{Elizabeth I.\} and Fane, \{Mitchell E.\} and Marino-Bravante, \{Gloria E.\} and Zabransky, \{Daniel J.\} and Cai, \{Kathy Q.\} and Jochen Utikal and Slusher, \{Barbara S.\} and Jeremy Walston and Lipson, \{Evan J.\} and Witwer, \{Kenneth W.\} and Weeraratna, \{Ashani T.\}",

year = "2024",

month = sep,

day = "24",

doi = "10.1016/j.celrep.2024.114721",

language = "English",

volume = "43",

journal = "Cell Reports",

issn = "2639-1856",

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Hüser, L, Chhabra, Y, Gololobova, O, Wang, V, Liu, G, Dixit, A, Rocha, MR, Harper, EI, Fane, ME, Marino-Bravante, GE, Zabransky, DJ, Cai, KQ, Utikal, J, Slusher, BS, Walston, J, Lipson, EJ, Witwer, KW & Weeraratna, AT 2024, 'Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma', Cell Reports, vol. 43, no. 9, 114721. https://doi.org/10.1016/j.celrep.2024.114721

TY - JOUR

T1 - Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma

AU - Hüser, Laura

AU - Chhabra, Yash

AU - Gololobova, Olesia

AU - Wang, Vania

AU - Liu, Guanshu

AU - Dixit, Agrani

AU - Rocha, Murilo Ramos

AU - Harper, Elizabeth I.

AU - Fane, Mitchell E.

AU - Marino-Bravante, Gloria E.

AU - Zabransky, Daniel J.

AU - Cai, Kathy Q.

AU - Utikal, Jochen

AU - Slusher, Barbara S.

AU - Walston, Jeremy

AU - Lipson, Evan J.

AU - Witwer, Kenneth W.

AU - Weeraratna, Ashani T.

PY - 2024/9/24

Y1 - 2024/9/24

N2 - 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.

AB - 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.

KW - aging

KW - angioepoetin ligand 2 (ANGPTL2)

KW - angiogenesis

KW - CD9

KW - CP: Cancer

KW - exosomes

KW - extracellular vesicles

KW - fibroblasts

KW - melanoma

KW - Aging/metabolism

KW - Humans

KW - Tumor Microenvironment

KW - Tetraspanin 29/metabolism

KW - Extracellular Vesicles/metabolism

KW - Melanoma/metabolism

KW - Skin Neoplasms/pathology

KW - Angiogenesis

KW - Endothelial Cells/metabolism

KW - Animals

KW - Fibroblasts/metabolism

KW - Neovascularization, Pathologic/metabolism

KW - Cell Line, Tumor

UR - https://www.scopus.com/pages/publications/85205275109

U2 - 10.1016/j.celrep.2024.114721

DO - 10.1016/j.celrep.2024.114721

M3 - Article

C2 - 39255061

AN - SCOPUS:85205275109

SN - 2639-1856

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 114721

ER -

Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma

Abstract

UN SDGs

Keywords

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