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.
Ayuko Hoshino  1 ,  Han Sang Kim  2 ,  Linda Bojmar  3 ,  Kofi Ennu Gyan  4 ,  Michele Cioffi  5 ,  Jonathan Hernandez  6 ,  Constantinos P Zambirinis  7 ,  Gonçalo Rodrigues  8 ,  Henrik Molina  9 ,  Søren Heissel  9 ,  Milica Tesic Mark  9 ,  Loïc Steiner  10 ,  Alberto Benito-Martin  5 ,  Serena Lucotti  5 ,  Angela Di Giannatale  11 ,  Katharine Offer  5 ,  Miho Nakajima  5 ,  Caitlin Williams  5 ,  Laura Nogués  12 ,  Fanny A Pelissier Vatter  5 ,  Ayako Hashimoto  13 ,  Alexander E Davies  14 ,  Daniela Freitas  15 ,  Candia M Kenific  5 ,  Yonathan Ararso  5 ,  Weston Buehring  5 ,  Pernille Lauritzen  5 ,  Yusuke Ogitani  5 ,  Kei Sugiura  16 ,  Naoko Takahashi  17 ,  Maša Alečković  18 ,  Kayleen A Bailey  5 ,  Joshua S Jolissant  7 ,  Huajuan Wang  5 ,  Ashton Harris  5 ,  L Miles Schaeffer  5 ,  Guillermo García-Santos  19 ,  Zoe Posner  5 ,  Vinod P Balachandran  20 ,  Yasmin Khakoo  21 ,  G Praveen Raju  22 ,  Avigdor Scherz  23 ,  Irit Sagi  24 ,  Ruth Scherz-Shouval  25 ,  Yosef Yarden  24 ,  Moshe Oren  26 ,  Mahathi Malladi  21 ,  Mary Petriccione  21 ,  Kevin C De Braganca  21 ,  Maria Donzelli  21 ,  Cheryl Fischer  21 ,  Stephanie Vitolano  21 ,  Geraldine P Wright  21 ,  Lee Ganshaw  21 ,  Mariel Marrano  21 ,  Amina Ahmed  21 ,  Joe DeStefano  21 ,  Enrico Danzer  27 ,  Michael H A Roehrl  28 ,  Norman J Lacayo  29 ,  Theresa C Vincent  30 ,  Martin R Weiser  31 ,  Mary S Brady  32 ,  Paul A Meyers  21 ,  Leonard H Wexler  21 ,  Srikanth R Ambati  21 ,  Alexander J Chou  21 ,  Emily K Slotkin  21 ,  Shakeel Modak  21 ,  Stephen S Roberts  21 ,  Ellen M Basu  21 ,  Daniel Diolaiti  33 ,  Benjamin A Krantz  34 ,  Fatima Cardoso  35 ,  Amber L Simpson  36 ,  Michael Berger  28 ,  Charles M Rudin  37 ,  Diane M Simeone  33 ,  Maneesh Jain  38 ,  Cyrus M Ghajar  39 ,  Surinder K Batra  38 ,  Ben Z Stanger  40 ,  Jack Bui  41 ,  Kristy A Brown  42 ,  Vinagolu K Rajasekhar  43 ,  John H Healey  43 ,  Maria de Sousa  8 ,  Kim Kramer  21 ,  Sujit Sheth  44 ,  Jeanine Baisch  45 ,  Virginia Pascual  45 ,  Todd E Heaton  27 ,  Michael P La Quaglia  27 ,  David J Pisapia  46 ,  Robert Schwartz  47 ,  Haiying Zhang  5 ,  Yuan Liu  48 ,  Arti Shukla  49 ,  Laurence Blavier  50 ,  Yves A DeClerck  50 ,  Mark LaBarge  51 ,  Mina J Bissell  52 ,  Thomas C Caffrey  38 ,  Paul M Grandgenett  38 ,  Michael A Hollingsworth  38 ,  Jacqueline Bromberg  53 ,  Bruno Costa-Silva  54 ,  Hector Peinado  55 ,  Yibin Kang  18 ,  Benjamin A Garcia  56 ,  Eileen M O'Reilly  37 ,  David Kelsen  37 ,  Tanya M Trippett  21 ,  David R Jones  48 ,  Irina R Matei  5 ,  William R Jarnagin  57 ,  David Lyden  58
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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 32795414 DOI: 10.1016/j.cell.2020.07.009
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.
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