title: Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles.
abstract: Large oncosomes (LO) are atypically large (1-10 µm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrep(TM)) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5th percentile) and was used to develop an assay to detect LO in the circulation and tissues of mice and patients with prostate cancer. These observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers.
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Valentina R
authors: VR
authors: Minciacchi
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Sungyong
authors: S
authors: You
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Cristiana
authors: C
authors: Spinelli
authors: The Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors: Samantha
authors: S
authors: Morley
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Mandana
authors: M
authors: Zandian
authors: Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Paul-Joseph
authors: PJ
authors: Aspuria
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.
authors: Lorenzo
authors: L
authors: Cavallini
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Experimental Pharmacology Unit, Department of Research, IRCCS-Istituto Nazionale Tumori G. Pascale, Naples, Italy.
authors: Chiara
authors: C
authors: Ciardiello
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Mariana
authors: M
authors: Reis Sobreiro
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Matteo
authors: M
authors: Morello
authors: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, BC, Canada.
authors: Geetanjali
authors: G
authors: Kharmate
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors: Su Chul
authors: SC
authors: Jang
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors: Dae-Kyum
authors: DK
authors: Kim
authors: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, BC, Canada.
authors: Elham
authors: E
authors: Hosseini-Beheshti
authors: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, BC, Canada.
authors: Emma
authors: E
authors: Tomlinson Guns
authors: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, BC, Canada.
authors: Martin
authors: M
authors: Gleave
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors: Yong Song
authors: YS
authors: Gho
authors: Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia.
authors: Suresh
authors: S
authors: Mathivanan
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Wei
authors: W
authors: Yang
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|The Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors: Michael R
authors: MR
authors: Freeman
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|The Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors: Dolores
authors: D
authors: Di Vizio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism* / Q000473:pathology; D002498:Centrifugation; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D000080865:Formins; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D053538:Keratin-18 / Q000378:metabolism; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053141:Organelle Size; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C484571:DIAPH3 protein, human; D000080865:Formins; C488421:KRT18 protein, human; D053538:Keratin-18; D009363:Neoplasm Proteins; D005973:Glutamine
keywords: SILAC Proteomics; amoeboid blebbing; cancer metabolism; extracellular vesicles; tumor progression