Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma
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.
Authors
- Олеся Гололобова (ORCID: https://orcid.org/0000-0002-0392-268X)
- Daniel J. Zabransky (ORCID: https://orcid.org/0000-0002-8184-3346)
- Jochen Sven Utikal (ORCID: https://orcid.org/0000-0001-5316-0241)
- Evan J. Lipson (ORCID: https://orcid.org/0000-0003-2976-0911)
- Barbara Stauch Slusher (ORCID: https://orcid.org/0000-0001-9814-4157)
- Murilo Ramos Rocha (ORCID: https://orcid.org/0000-0001-5499-6374)
- Yash Chhabra (ORCID: https://orcid.org/0000-0003-2883-4675)
- Vania Wang (ORCID: https://orcid.org/0000-0002-9428-7019)
- Gloria E Marino-Bravante (ORCID: https://orcid.org/0000-0003-4733-0122)
- Guanshu Liu (ORCID: https://orcid.org/0000-0002-8188-4332)
- Mitchell E. Fane (ORCID: https://orcid.org/0000-0001-6163-5753)
- Kenneth Whitaker Witwer (ORCID: https://orcid.org/0000-0003-1664-4233)
- Kathy Q. Cai (ORCID: https://orcid.org/0000-0002-6034-3377)
- Ashani T. Weeraratna (ORCID: https://orcid.org/0000-0003-0448-6952)
- Jeremy Walston (ORCID: https://orcid.org/0000-0002-6965-2723)
- Laura Hüser (ORCID: https://orcid.org/0000-0001-7599-8192)
- Elizabeth I. Harper (ORCID: https://orcid.org/0000-0002-3547-1692)
- Agrani Dixit (ORCID: https://orcid.org/0000-0002-4983-8256)
Institutions
- Fox Chase Cancer Center (US)
- Johns Hopkins University (US)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Johns Hopkins Medicine (US)
- University Hospital Heidelberg (DE)
- Sidney Kimmel Cancer Center (US)
- University Medical Centre Mannheim (DE)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114721
- Citations
- 13
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- Conquer Cancer Foundation
- Melanoma Research Alliance
- Johns Hopkins University
- Cholangiocarcinoma Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Genentech
- University of Texas MD Anderson Cancer Center
- National Institute on Aging
- National Institute of Mental Health
- National Cancer Institute
- Moonshot Research and Development Program
- Cancer Moonshot