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

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 VatterAyako 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

Research output: Contribution to journal › Article › peer-review

456 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1044-1061.e18
Journal	Cell
Volume	182
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2020.07.009
State	Published - Aug 20 2020

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

Keywords

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

Access to Document

10.1016/j.cell.2020.07.009

Cite this

Hoshino, A., Kim, H. S., Bojmar, L., Gyan, K. E., Cioffi, M., Hernandez, J., Zambirinis, C. P., Rodrigues, G., Molina, H., Heissel, S., Mark, M. T., Steiner, L., Benito-Martin, A., Lucotti, S., Di Giannatale, A., Offer, K., Nakajima, M., Williams, C., Nogués, L., ... Lyden, D. (2020). Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers. Cell, 182(4), 1044-1061.e18. https://doi.org/10.1016/j.cell.2020.07.009

@article{b6aa4db64cc64f73bbcacd110859fc53,

title = "Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers",

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",

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

note = "Funding Information: 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{\textquoteright}s Consortium (to T.T., D.L., M.H.R., M.B., M.P.L., T.H., and S.A.), Alex{\textquoteright}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.). Funding Information: 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.). A. Hoshino designed the experimental approach, coordinated the project, interpreted the data, and wrote the manuscript. H.S.K. designed the experimental approach and analyzed data. L. Bojmar coordinated the PaCa sample preparation and data collection, performed validation experiments, and revised the manuscript. K.E.G. analyzed data. M.C. S.L. K.S. and N.T. performed validation experiments. J.H. C.P.Z. G.R. L.S. Y.L. A.D.G. K.O. and M.N. coordinated the sample preparation and data collection. M.T.M. H.M. S.H. P.L. B.A.G. Y. Kang, and M.A. performed proteomics analyses. A.B.-M. performed NTA analysis and sample collection. C.W. A. Hashimoto, F.A.P.V. A.E.D. I.R.M. Y.A. G.R. L. Blavier, D.F. L.N. Y.O. and W.B. processed samples. M.J.B. provided human normal breast cells. V.K.R. and J.H.H. provided patient samples. H.W. L.M.S. Z.P. V.P.B. Y. Khakoo, G.P.R. A. Scherz. I.S. R.S.-S. Y.Y. G.G.-S. M.M. T.C.C. M.P. K.C.D.B. M.D. C.F. S.V. G.W. L.G. M.M. A.A. J.D. J.S.J. E.D. M.H.R. T.C.V. M.R.W. M.S.B. P.A.M. L.H.W. S.R.A. A.J.C. E.K.S. S.M. S.S.R. E.M.B. D.D. B.A.K. F.C. A.L.S. M.B. C.M.R. D.M.S. M.J. S.K.B. J. Bui, K.A. Brown, K.A. Bailey, D.K. K.K. S.S. J. Baisch, V.P. T.E.H. M.P.L.Q. D.J.P. A. Shukla. P.M.G. M.A.H. B.Z.S. and E.M.O.R. provided human samples. T.M.T. coordinated pediatric studies and D.R.J. coordinated LuCa studies and provided human samples. W.R.J. discussed the hypothesis, led, and coordinated PaCa studies. A. Harris, J.S.J, R.S. C.M.K. H.Z. Y.D.C. M.L.B. C.M.G. H.P. B.C.-S. J. Bromberg, M.O. N.J.L. and M.d.S. read the manuscript and provided feedback. I.R.M. coordinated sample acquisition, processing, data collection, discussed the hypothesis, contributed to data interpretation, and wrote the manuscript. D.L. conceived the hypothesis, led the project, interpreted the data, and wrote the manuscript. D.L. A.H. H.S.K. and L.B. have filed a U.S. patent application related to this work. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = aug,

day = "20",

doi = "10.1016/j.cell.2020.07.009",

language = "English (US)",

volume = "182",

pages = "1044--1061.e18",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "4",

}

Hoshino, A, Kim, HS, Bojmar, L, Gyan, KE, Cioffi, M, Hernandez, J, Zambirinis, CP, Rodrigues, G, Molina, H, Heissel, S, Mark, MT, Steiner, L, Benito-Martin, A, Lucotti, S, Di Giannatale, A, Offer, K, Nakajima, M, Williams, C, Nogués, L, Pelissier Vatter, FA, Hashimoto, A, Davies, AE, Freitas, D, Kenific, CM, Ararso, Y, Buehring, W, Lauritzen, P, Ogitani, Y, Sugiura, K, Takahashi, N, Alečković, M, Bailey, KA, Jolissant, JS, Wang, H, Harris, A, Schaeffer, LM, García-Santos, G, Posner, Z, Balachandran, VP, Khakoo, Y, Raju, GP, Scherz, A, Sagi, I, Scherz-Shouval, R, Yarden, Y, Oren, M, Malladi, M, Petriccione, M, De Braganca, KC, Donzelli, M, Fischer, C, Vitolano, S, Wright, GP, Ganshaw, L, Marrano, M, Ahmed, A, DeStefano, J, Danzer, E, Roehrl, MHA, Lacayo, NJ, Vincent, TC, Weiser, MR, Brady, MS, Meyers, PA, Wexler, LH, Ambati, SR, Chou, AJ, Slotkin, EK, Modak, S, Roberts, SS, Basu, EM, Diolaiti, D, Krantz, BA, Cardoso, F, Simpson, AL, Berger, M, Rudin, CM, Simeone, DM, Jain, M, Ghajar, CM, Batra, SK, Stanger, BZ, Bui, J, Brown, KA, Rajasekhar, VK, Healey, JH, de Sousa, M, Kramer, K, Sheth, S, Baisch, J, Pascual, V, Heaton, TE, La Quaglia, MP, Pisapia, DJ, Schwartz, R, Zhang, H, Liu, Y, Shukla, A, Blavier, L, DeClerck, YA, LaBarge, M, Bissell, MJ, Caffrey, TC, Grandgenett, PM, Hollingsworth, MA, Bromberg, J, Costa-Silva, B, Peinado, H, Kang, Y, Garcia, BA, O'Reilly, EM, Kelsen, D, Trippett, TM, Jones, DR, Matei, IR, Jarnagin, WR & Lyden, D 2020, 'Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers', Cell, vol. 182, no. 4, pp. 1044-1061.e18. https://doi.org/10.1016/j.cell.2020.07.009

TY - JOUR

T1 - Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers

AU - Hoshino, Ayuko

AU - Kim, Han Sang

AU - Bojmar, Linda

AU - Gyan, Kofi Ennu

AU - Cioffi, Michele

AU - Hernandez, Jonathan

AU - Zambirinis, Constantinos P.

AU - Rodrigues, Gonçalo

AU - Molina, Henrik

AU - Heissel, Søren

AU - Mark, Milica Tesic

AU - Steiner, Loïc

AU - Benito-Martin, Alberto

AU - Lucotti, Serena

AU - Di Giannatale, Angela

AU - Offer, Katharine

AU - Nakajima, Miho

AU - Williams, Caitlin

AU - Nogués, Laura

AU - Pelissier Vatter, Fanny A.

AU - Hashimoto, Ayako

AU - Davies, Alexander E.

AU - Freitas, Daniela

AU - Kenific, Candia M.

AU - Ararso, Yonathan

AU - Buehring, Weston

AU - Lauritzen, Pernille

AU - Ogitani, Yusuke

AU - Sugiura, Kei

AU - Takahashi, Naoko

AU - Alečković, Maša

AU - Bailey, Kayleen A.

AU - Jolissant, Joshua S.

AU - Wang, Huajuan

AU - Harris, Ashton

AU - Schaeffer, L. Miles

AU - García-Santos, Guillermo

AU - Posner, Zoe

AU - Balachandran, Vinod P.

AU - Khakoo, Yasmin

AU - Raju, G. Praveen

AU - Scherz, Avigdor

AU - Sagi, Irit

AU - Scherz-Shouval, Ruth

AU - Yarden, Yosef

AU - Oren, Moshe

AU - Malladi, Mahathi

AU - Petriccione, Mary

AU - De Braganca, Kevin C.

AU - Donzelli, Maria

AU - Fischer, Cheryl

AU - Vitolano, Stephanie

AU - Wright, Geraldine P.

AU - Ganshaw, Lee

AU - Marrano, Mariel

AU - Ahmed, Amina

AU - DeStefano, Joe

AU - Danzer, Enrico

AU - Roehrl, Michael H.A.

AU - Lacayo, Norman J.

AU - Vincent, Theresa C.

AU - Weiser, Martin R.

AU - Brady, Mary S.

AU - Meyers, Paul A.

AU - Wexler, Leonard H.

AU - Ambati, Srikanth R.

AU - Chou, Alexander J.

AU - Slotkin, Emily K.

AU - Modak, Shakeel

AU - Roberts, Stephen S.

AU - Basu, Ellen M.

AU - Diolaiti, Daniel

AU - Krantz, Benjamin A.

AU - Cardoso, Fatima

AU - Simpson, Amber L.

AU - Berger, Michael

AU - Rudin, Charles M.

AU - Simeone, Diane M.

AU - Jain, Maneesh

AU - Ghajar, Cyrus M.

AU - Batra, Surinder K.

AU - Stanger, Ben Z.

AU - Bui, Jack

AU - Brown, Kristy A.

AU - Rajasekhar, Vinagolu K.

AU - Healey, John H.

AU - de Sousa, Maria

AU - Kramer, Kim

AU - Sheth, Sujit

AU - Baisch, Jeanine

AU - Pascual, Virginia

AU - Heaton, Todd E.

AU - La Quaglia, Michael P.

AU - Pisapia, David J.

AU - Schwartz, Robert

AU - Zhang, Haiying

AU - Liu, Yuan

AU - Shukla, Arti

AU - Blavier, Laurence

AU - DeClerck, Yves A.

AU - LaBarge, Mark

AU - Bissell, Mina J.

AU - Caffrey, Thomas C.

AU - Grandgenett, Paul M.

AU - Hollingsworth, Michael A.

AU - Bromberg, Jacqueline

AU - Costa-Silva, Bruno

AU - Peinado, Hector

AU - Kang, Yibin

AU - Garcia, Benjamin A.

AU - O'Reilly, Eileen M.

AU - Kelsen, David

AU - Trippett, Tanya M.

AU - Jones, David R.

AU - Matei, Irina R.

AU - Jarnagin, William R.

AU - Lyden, David

N1 - Funding Information: 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.). Funding Information: 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.). A. Hoshino designed the experimental approach, coordinated the project, interpreted the data, and wrote the manuscript. H.S.K. designed the experimental approach and analyzed data. L. Bojmar coordinated the PaCa sample preparation and data collection, performed validation experiments, and revised the manuscript. K.E.G. analyzed data. M.C. S.L. K.S. and N.T. performed validation experiments. J.H. C.P.Z. G.R. L.S. Y.L. A.D.G. K.O. and M.N. coordinated the sample preparation and data collection. M.T.M. H.M. S.H. P.L. B.A.G. Y. Kang, and M.A. performed proteomics analyses. A.B.-M. performed NTA analysis and sample collection. C.W. A. Hashimoto, F.A.P.V. A.E.D. I.R.M. Y.A. G.R. L. Blavier, D.F. L.N. Y.O. and W.B. processed samples. M.J.B. provided human normal breast cells. V.K.R. and J.H.H. provided patient samples. H.W. L.M.S. Z.P. V.P.B. Y. Khakoo, G.P.R. A. Scherz. I.S. R.S.-S. Y.Y. G.G.-S. M.M. T.C.C. M.P. K.C.D.B. M.D. C.F. S.V. G.W. L.G. M.M. A.A. J.D. J.S.J. E.D. M.H.R. T.C.V. M.R.W. M.S.B. P.A.M. L.H.W. S.R.A. A.J.C. E.K.S. S.M. S.S.R. E.M.B. D.D. B.A.K. F.C. A.L.S. M.B. C.M.R. D.M.S. M.J. S.K.B. J. Bui, K.A. Brown, K.A. Bailey, D.K. K.K. S.S. J. Baisch, V.P. T.E.H. M.P.L.Q. D.J.P. A. Shukla. P.M.G. M.A.H. B.Z.S. and E.M.O.R. provided human samples. T.M.T. coordinated pediatric studies and D.R.J. coordinated LuCa studies and provided human samples. W.R.J. discussed the hypothesis, led, and coordinated PaCa studies. A. Harris, J.S.J, R.S. C.M.K. H.Z. Y.D.C. M.L.B. C.M.G. H.P. B.C.-S. J. Bromberg, M.O. N.J.L. and M.d.S. read the manuscript and provided feedback. I.R.M. coordinated sample acquisition, processing, data collection, discussed the hypothesis, contributed to data interpretation, and wrote the manuscript. D.L. conceived the hypothesis, led the project, interpreted the data, and wrote the manuscript. D.L. A.H. H.S.K. and L.B. have filed a U.S. patent application related to this work. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/8/20

Y1 - 2020/8/20

N2 - 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.

AB - 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.

KW - biomarkers

KW - cancer

KW - cancer of unknown primary origin

KW - damage-associated molecular patterns

KW - early cancer detection

KW - exomeres

KW - exosomes

KW - extracellular vesicles and particles

KW - liquid biopsy

KW - proteomics

UR - http://www.scopus.com/inward/record.url?scp=85089433166&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85089433166&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.07.009

DO - 10.1016/j.cell.2020.07.009

M3 - Article

C2 - 32795414

AN - SCOPUS:85089433166

SN - 0092-8674

VL - 182

SP - 1044-1061.e18

JO - Cell

JF - Cell

IS - 4

ER -

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers

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