Hoshino, AyukoKim, Han SangBojmar, LindaGyan, Kofi EnnuCioffi, MicheleHernandez, JonathanZambirinis, Constantinos PRodrigues, GonçaloMolina, HenrikHeissel, SørenMark, Milica TesicSteiner, LoïcBenito-Martin, AlbertoLucotti, SerenaDi Giannatale, AngelaOffer, KatharineNakajima, MihoWilliams, CaitlinNogués, LauraPelissier Vatter, Fanny AHashimoto, AyakoDavies, Alexander EFreitas, DanielaKenific, Candia MArarso, YonathanBuehring, WestonLauritzen, PernilleOgitani, YusukeSugiura, KeiTakahashi, NaokoAlečković, MašaBailey, Kayleen AJolissant, Joshua SWang, HuajuanHarris, AshtonSchaeffer, L MilesGarcía-Santos, GuillermoPosner, ZoeBalachandran, Vinod PKhakoo, YasminRaju, G PraveenScherz, AvigdorSagi, IritScherz-Shouval, RuthYarden, YosefOren, MosheMalladi, MahathiPetriccione, MaryDe Braganca, Kevin CDonzelli, MariaFischer, CherylVitolano, StephanieWright, Geraldine PGanshaw, LeeMarrano, MarielAhmed, AminaDeStefano, JoeDanzer, EnricoRoehrl, Michael H ALacayo, Norman JVincent, Theresa CWeiser, Martin RBrady, Mary SMeyers, Paul AWexler, Leonard HAmbati, Srikanth RChou, Alexander JSlotkin, Emily KModak, ShakeelRoberts, Stephen SBasu, Ellen MDiolaiti, DanielKrantz, Benjamin ACardoso, FatimaSimpson, Amber LBerger, MichaelRudin, Charles MSimeone, Diane MJain, ManeeshGhajar, Cyrus MBatra, Surinder KStanger, Ben ZBui, JackBrown, Kristy ARajasekhar, Vinagolu KHealey, John Hde Sousa, MariaKramer, KimSheth, SujitBaisch, JeaninePascual, VirginiaHeaton, Todd ELa Quaglia, Michael PPisapia, David JSchwartz, RobertZhang, HaiyingLiu, YuanShukla, ArtiBlavier, LaurenceDeClerck, Yves ALaBarge, MarkBissell, Mina JCaffrey, Thomas CGrandgenett, Paul MHollingsworth, Michael ABromberg, JacquelineCosta-Silva, BrunoPeinado Selgas, HectorKang, YibinGarcia, Benjamin AO'Reilly, Eileen MKelsen, DavidTrippett, Tanya MJones, David RMatei, Irina RJarnagin, William RLyden, David2025-01-072025-01-072020-08-20Cell . 2020 Aug 20;182(4):1044-1061https://hdl.handle.net/20.500.12105/25959There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.This work is dedicated to Maria de Sousa, Emeritus Professor at the University of Porto, Adjunct Professor in Pediatrics at Weill Cornell Medicine, and co-founder of the prestigious "Graduate Program in Basic and Applied Biology (GABBA)'' at the University of Porto, who succumbed to COVID-19 on April 14, 2020. Maria was a noted immunologist who pioneered studies in lymphocyte migration, defining the concept of "ecotaxis.'' We honor her last wish: "In your living the hope of my lasting.'' We thank the Mesothelioma Research Bank (CDC NIOSH 1-U19-OH009077-01 NMVP) for plasma samples, Medical Illustration & Design Services of Yonsei University College of Medicine for the art, and the Electron Microscopy & Histology services of the Weill Cornell Medicine Microscopy & Image Analysis Core for TEM with NIH Shared Instrumentation Grant (S10RR027699). The authors gratefully acknowledge support from the National Cancer Institute (CA224175 to D.L. and V.P.B., CA210240 to D.L. and M.H., CA232093 to D.L., CA163117 and CA207983 to D.L. and Y.D.C., CA163120 to D.L. and S.K.B., CA169416 to D.L. and H.P., CA169538 to D.L. and M.J.B., CA218513 to D.L. and H.Z., and AI144301 to D.L. and V.P.), the United States Department of Defense (W81XWH-13-1-0425 to D.L. and Y.K., W81XWH-13-1-0427 and W81XWH-13-1-0249 to D.L., and W81XWH-14-1-0199 to D.L. and A.S., the Melanoma Research Alliance (to H.P), the Hartwell Foundation (to D.L. and J.B.), the Thompson Family Foundation (to D.K., A.S., D.L., R.S., Y.Y., I.S., R.S.S., V.P.B., and E.O.), the STARR Consortium (I9-A9-056 to D.L., P.R., K.K., and H.Z. and I8-A8-123 to D.L. and H.P.), the Pediatric Oncology Experimental Therapeutics Investigator's Consortium (to T.T., D.L., M.H.R., M.B., M.P.L., T.H., and S.A.), Alex's Lemonade Stand Foundation (to D.L. and P.R.), the Breast Cancer Research Foundation (to D.L., M.J.B., and C.M.G.), the Feldstein Medical Foundation (to D.L. and H.P.), the Tortolani Foundation (to D.L. and J.B.), the Clinical & Translational Science Center (to D.L. and H.Z.), the Mary Kay Ash Charitable Foundation (to D.L. and I.M.), the Malcolm Hewitt Weiner Foundation, the Manning Foundation, the Daniel P. and Nancy C. Paduano Family Foundation, the James Paduano Foundation, the Sohn Foundation, the AHEPA Vth District Cancer Research Foundation, the Daedalus Fund, Selma and Lawrence Ruben Science to Industry Bridge Award, the Children's Cancer and Blood Foundation (to D.L.), the Scott and Lisa Stuart Family Foundation, the D10 Foundation (to T.T.), Susan G. Komen Postdoctoral Fellowship (PDF15331556, JST PRESTO 30021, and JSPS KAKENHI JP19K23743 to A.H.), the National Research Foundation of Korea (2019R1C1C1006709 and 2018R1A5A2025079 [MSIT]), Severance Hospital Research fund for Clinical Excellence (C-2019-0026), faculty research grant of Yonsei University College of Medicine (6-2019-0090), Daewoong Foundation Research Grant (to H.S.K.), the Swedish Cancer Society Pancreatic Cancer Fellowship (to L.B.), the Lions International Postdoctoral fellowship (to L.B.), the Sweden-America stipend (to L.B.), the Memorial Sloan Kettering Cancer Center Metastasis and Tumor Ecosystems Center fellowship (to C.P.Z.), the Weill Cornell Medical College Clinical and Translational Science Center funded by NIH/NCATS (UL1TR002384 to J.S.J.), the "Little Eric Foundation'' (to Y.K.), and the EVAN Foundation (to K.K.).engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/biomarkerscancercancer of unknown primary origindamage-associated molecular patternsearly cancer detectionexomeresexosomesextracellular vesicles and particlesliquid biopsyproteomicsAttribution-NonCommercial-NoDerivatives 4.0 International3279541418241044-1061Cellhttps://pmc.ncbi.nlm.nih.gov/articles/PMC7522766/pdf/nihms-1612511.pdfopen access