Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers

Ayuko Hoshino; Han Sang Kim; Linda Bojmar; Kofi Ennu Gyan; Michele Cioffi; Jonathan Hernandez; Constantinos P Zambirinis; Gonçalo Rodrigues; Henrik Molina; Søren Heissel; Milica Tesic Mark; Loïc Steiner; Alberto Benito-Martin; Serena Lucotti; Angela Di Giannatale; Katharine Offer; Miho Nakajima; Caitlin Williams; Laura Nogués; Fanny A Pelissier Vatter; Ayako Hashimoto; Alexander E Davies; Daniela Freitas; Candia M Kenific; Yonathan Ararso; Weston Buehring; Pernille Lauritzen; Yusuke Ogitani; Kei Sugiura; Naoko Takahashi; Maša Alečković; Kayleen A Bailey; Joshua S Jolissant; Huajuan Wang; Ashton Harris; L Miles Schaeffer; Guillermo García-Santos; Zoe Posner; Vinod P Balachandran; Yasmin Khakoo; G Praveen Raju; Avigdor Scherz; Irit Sagi; Ruth Scherz-Shouval; Yosef Yarden; Moshe Oren; Mahathi Malladi; Mary Petriccione; Kevin C De Braganca; Maria Donzelli; Cheryl Fischer; Stephanie Vitolano; Geraldine P Wright; Lee Ganshaw; Mariel Marrano; Amina Ahmed; Joe DeStefano; Enrico Danzer; Michael H A Roehrl; Norman J Lacayo; Theresa C Vincent; Martin R Weiser; Mary S Brady; Paul A Meyers; Leonard H Wexler; Srikanth R Ambati; Alexander J Chou; Emily K Slotkin; Shakeel Modak; Stephen S Roberts; Ellen M Basu; Daniel Diolaiti; Benjamin A Krantz; Fatima Cardoso; Amber L Simpson; Michael Berger; Charles M Rudin; Diane M Simeone; Maneesh Jain; Cyrus M Ghajar; Surinder K Batra; Ben Z Stanger; Jack Bui; Kristy A Brown; Vinagolu K Rajasekhar; John H Healey; Maria de Sousa; Kim Kramer; Sujit Sheth; Jeanine Baisch; Virginia Pascual; Todd E Heaton; Michael P La Quaglia; David J Pisapia; Robert Schwartz; Haiying Zhang; Yuan Liu; Arti Shukla; Laurence Blavier; Yves A DeClerck; Mark LaBarge; Mina J Bissell; Thomas C Caffrey; Paul M Grandgenett; Michael A Hollingsworth; Jacqueline Bromberg; Bruno Costa-Silva; Hector Peinado; Yibin Kang; Benjamin A Garcia; Eileen M O'Reilly; David Kelsen; Tanya M Trippett; David R Jones; Irina R Matei; William R Jarnagin; David Lyden

doi:10.1016/j.cell.2020.07.009

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers

Cell. 2020 Aug 20;182(4):1044-1061.e18. doi: 10.1016/j.cell.2020.07.009. Epub 2020 Aug 13.

Authors

Ayuko Hoshino¹, Han Sang Kim², Linda Bojmar³, Kofi Ennu Gyan⁴, Michele Cioffi⁵, Jonathan Hernandez⁶, Constantinos P Zambirinis⁷, Gonçalo Rodrigues⁸, Henrik Molina⁹, Søren Heissel⁹, Milica Tesic Mark⁹, Loïc Steiner¹⁰, Alberto Benito-Martin⁵, Serena Lucotti⁵, Angela Di Giannatale¹¹, Katharine Offer⁵, Miho Nakajima⁵, Caitlin Williams⁵, Laura Nogués¹², Fanny A Pelissier Vatter⁵, Ayako Hashimoto¹³, Alexander E Davies¹⁴, Daniela Freitas¹⁵, Candia M Kenific⁵, Yonathan Ararso⁵, Weston Buehring⁵, Pernille Lauritzen⁵, Yusuke Ogitani⁵, Kei Sugiura¹⁶, Naoko Takahashi¹⁷, Maša Alečković¹⁸, Kayleen A Bailey⁵, Joshua S Jolissant⁷, Huajuan Wang⁵, Ashton Harris⁵, L Miles Schaeffer⁵, Guillermo García-Santos¹⁹, Zoe Posner⁵, Vinod P Balachandran²⁰, Yasmin Khakoo²¹, G Praveen Raju²², Avigdor Scherz²³, Irit Sagi²⁴, Ruth Scherz-Shouval²⁵, Yosef Yarden²⁴, Moshe Oren²⁶, Mahathi Malladi²¹, Mary Petriccione²¹, Kevin C De Braganca²¹, Maria Donzelli²¹, Cheryl Fischer²¹, Stephanie Vitolano²¹, Geraldine P Wright²¹, Lee Ganshaw²¹, Mariel Marrano²¹, Amina Ahmed²¹, Joe DeStefano²¹, Enrico Danzer²⁷, Michael H A Roehrl²⁸, Norman J Lacayo²⁹, Theresa C Vincent³⁰, Martin R Weiser³¹, Mary S Brady³², Paul A Meyers²¹, Leonard H Wexler²¹, Srikanth R Ambati²¹, Alexander J Chou²¹, Emily K Slotkin²¹, Shakeel Modak²¹, Stephen S Roberts²¹, Ellen M Basu²¹, Daniel Diolaiti³³, Benjamin A Krantz³⁴, Fatima Cardoso³⁵, Amber L Simpson³⁶, Michael Berger²⁸, Charles M Rudin³⁷, Diane M Simeone³³, Maneesh Jain³⁸, Cyrus M Ghajar³⁹, Surinder K Batra³⁸, Ben Z Stanger⁴⁰, Jack Bui⁴¹, Kristy A Brown⁴², Vinagolu K Rajasekhar⁴³, John H Healey⁴³, Maria de Sousa⁸, Kim Kramer²¹, Sujit Sheth⁴⁴, Jeanine Baisch⁴⁵, Virginia Pascual⁴⁵, Todd E Heaton²⁷, Michael P La Quaglia²⁷, David J Pisapia⁴⁶, Robert Schwartz⁴⁷, Haiying Zhang⁵, Yuan Liu⁴⁸, Arti Shukla⁴⁹, Laurence Blavier⁵⁰, Yves A DeClerck⁵⁰, Mark LaBarge⁵¹, Mina J Bissell⁵², Thomas C Caffrey³⁸, Paul M Grandgenett³⁸, Michael A Hollingsworth³⁸, Jacqueline Bromberg⁵³, Bruno Costa-Silva⁵⁴, Hector Peinado⁵⁵, Yibin Kang¹⁸, Benjamin A Garcia⁵⁶, Eileen M O'Reilly³⁷, David Kelsen³⁷, Tanya M Trippett²¹, David R Jones⁴⁸, Irina R Matei⁵, William R Jarnagin⁵⁷, David Lyden⁵⁸

Affiliations

¹ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan; Japan Science and Technology Agency, PRESTO, Tokyo, Japan. Electronic address: ayukohoshino@bio.titech.ac.jp.
² Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Brain Korea 21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
³ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
⁴ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Tri-Institutional PhD Program in Computational Biology and Medicine, New York, NY, USA.
⁵ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
⁶ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD USA.
⁷ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
⁹ Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
¹⁰ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.
¹¹ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Pediatric Haematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
¹² Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
¹³ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan; Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
¹⁴ Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
¹⁵ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; i3S-Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, Porto, Portugal.
¹⁶ School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
¹⁷ School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.
¹⁸ Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
¹⁹ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of General and Gastrointestinal Surgery, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
²⁰ Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²¹ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²² Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²³ Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot, Israel.
²⁴ Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
²⁵ Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
²⁶ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
²⁷ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁸ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁹ Lucile Packard Children's Hospital Stanford, Stanford, CA, USA.
³⁰ Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden; Department of Microbiology, New York University School of Medicine, New York, NY, USA.
³¹ Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³² Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³³ Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
³⁴ Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁵ Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal.
³⁶ Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁷ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁸ Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
³⁹ Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴⁰ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴¹ Department of Pathology, University of California San Diego, La Jolla, CA, USA.
⁴² Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁴³ Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴⁴ Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
⁴⁵ Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health, Weill Cornell Medicine, New York, NY, USA.
⁴⁶ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
⁴⁷ Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY, USA.
⁴⁸ Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴⁹ Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA.
⁵⁰ Department of Pediatrics and Biochemistry and Molecular Medicine, University of Southern California, CA, USA.
⁵¹ Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA, USA.
⁵² Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
⁵³ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁵⁴ Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal.
⁵⁵ Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
⁵⁶ Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵⁷ Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: jarnagiw@mskcc.org.
⁵⁸ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: dcl2001@med.cornell.edu.

Abstract

There 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.

Keywords: biomarkers; cancer; cancer of unknown primary origin; damage-associated molecular patterns; early cancer detection; exomeres; exosomes; extracellular vesicles and particles; liquid biopsy; proteomics.

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

Animals
Biomarkers, Tumor / blood
Biomarkers, Tumor / metabolism*
Cell Line
Extracellular Vesicles / metabolism*
HSC70 Heat-Shock Proteins / metabolism
Humans
Machine Learning
Mice
Mice, Inbred C57BL
Microfilament Proteins / metabolism
Neoplasms / diagnosis*
Neoplasms / metabolism
Proteome / analysis
Proteome / metabolism
Proteomics / methods
Sensitivity and Specificity
Tetraspanin 29 / metabolism
rap GTP-Binding Proteins / metabolism

Substances

Biomarkers, Tumor
HSC70 Heat-Shock Proteins
HSPA8 protein, human
Microfilament Proteins
Proteome
Tetraspanin 29
moesin
RAP1B protein, human
rap GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding