Oncogene-regulated release of extracellular vesicles

Seda Kilinc; Rebekka Paisner; Roman Camarda; Suprit Gupta; Olga Momcilovic; Rebecca A Kohnz; Baris Avsaroglu; Noelle D L'Etoile; Rushika M Perera; Daniel K Nomura; Andrei Goga

doi:10.1016/j.devcel.2021.05.014

Oncogene-regulated release of extracellular vesicles

Dev Cell. 2021 Jul 12;56(13):1989-2006.e6. doi: 10.1016/j.devcel.2021.05.014. Epub 2021 Jun 11.

Authors

Affiliations

¹ Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: seda.kilinc@ucsf.edu.
² Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁶ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: andrei.goga@ucsf.edu.

Abstract

Oncogenes can alter metabolism by changing the balance between anabolic and catabolic processes. However, how oncogenes regulate tumor cell biomass remains poorly understood. Using isogenic MCF10A cells transformed with nine different oncogenes, we show that specific oncogenes reduce the biomass of cancer cells by promoting extracellular vesicle (EV) release. While MYC and AURKB elicited the highest number of EVs, each oncogene selectively altered the protein composition of released EVs. Likewise, oncogenes alter secreted miRNAs. MYC-overexpressing cells require ceramide, whereas AURKB requires ESCRT to release high levels of EVs. We identify an inverse relationship between MYC upregulation and activation of the RAS/MEK/ERK signaling pathway for regulating EV release in some tumor cells. Finally, lysosome genes and activity are downregulated in the context of MYC and AURKB, suggesting that cellular contents, instead of being degraded, were released via EVs. Thus, oncogene-mediated biomass regulation via differential EV release is a new metabolic phenotype.

Keywords: AURKB; ESCRT; EVs; HRAS; MYC; ceramide; extracellular vesicles; lysosome; miRNAs; oncogenes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aurora Kinase B / genetics*
Energy Metabolism / genetics
Extracellular Vesicles / genetics
Extracellular Vesicles / metabolism*
Gene Expression Regulation, Neoplastic
Genes, ras / genetics
Humans
Lysosomes / genetics
MAP Kinase Kinase Kinases / genetics
MAP Kinase Signaling System / genetics
Metabolism / genetics
Oncogenes / genetics*
Proto-Oncogene Proteins c-myc / genetics*
Signal Transduction / genetics

Substances

MYC protein, human
Proto-Oncogene Proteins c-myc
AURKB protein, human
Aurora Kinase B
MAP Kinase Kinase Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding