Dataset Information

Tissue- and plasma-derived exosomal protein 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 exosomes in 426 human samples from tissue explants (TE), plasma and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, HSP90AB1 represent pan-exosomes/exomeres. Moreover, we identified novel pan-exosome/exomere markers (e.g., ACTB, MSN, RAP1B). As proof of principle that exosomes are ideal diagnostic tools, we analyzed the proteome of TE exosomes (n=151) or plasma-derived exosomes (n=120). Comparison of TE exosomes identified proteins (e.g., VCAN, TNC, THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machinelearning classification of plasma-derived exosomes revealed 95% sensitivity/90% specificity in identifying cancer-associated exosomes. Finally, we defined a panel of tumor-type specific exosomal proteins in TE and plasma, which may help classify tumors of unknown primary origin. Overall, exosomal proteins can serve as reliable biomarkers for cancer detection and for determining cancer type

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive Plus, Q Exactive HF, Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Blood-lymph, Brain, Blood Plasma, Lung, Liver, Lymph Node, Kidney, Cell Culture, Blood Serum, Muscle, Skin, Colon, Pancreas, Bile Duct, Bone Marrow, Bile

DISEASE(S): Stomach Cancer,Prostate Adenocarcinoma,Uveal Melanoma,Embryonal Rhabdomyosarcoma,Melanoma,Renal Wilms' Tumor,Fibrosarcoma,Malignant Mesothelioma,Pancreatic Cancer,Neuroblastoma,Chronic Bronchitis,Synovial Sarcoma,Peripheral Primitive Neuroectodermal Tumor,Childhood Extraosseous Osteosarcoma,Acute Leukemia,Colon Cancer,Head And Neck Cancer,Brain Cancer,Retinoblastoma,Lung Carcinoma,Cholangiocarcinoma

SUBMITTER: henrik molina

LAB HEAD: David C. Lyden

PROVIDER: PXD018301 | Pride | 2020-08-17

REPOSITORIES: Pride

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Publications

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers.

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

Cell 20200813 4

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) ...[more]

PMID: 32795414

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Project description:Exososmes, potent intercellular communicators, are supposed to contribute to metastasis formation, which we confirmed for exosomes of the metastatic rat pancreatic adenocarcinoma line BSp73ASML that promote metastatic settlement in lymph nodes and lung of poorly metastatic BSp73ASML cells with a selective CD44v4-v7 (BSp73ASML-CD44vkd) knockdown. To define the molecular pathway(s), whereby exosomes contribute to premetastatic niche preparation, we profiled mRNA miRNA of BSp73ASMLwt and BSp73ASML-CD44vkd- exosomes and evaluated the impact on potential target cells. BSp73ASML exosomes are recovered in the draining lymph node after subcutaneous injection. In vitro, they preferentially bind and are taken-up by lymph node stroma cells (LnStr) and lung fibroblasts (LuFb) that were chosen as exosome targets. BSp73ASMLwt and BSp73ASML-CD44kd exosomes contain a restricted repertoire of mRNA and miRNA, hwere the lattter differe significantly between the two lines and even more pronounced, exosomes derived thereof with a not yet explored dominance of tumor-suppressor miRNA in ASML-CD44kd cells and exosomes. Both, exosomal mRNA and miRNA are recovered in target cells and exosome-uptake is accompanied by significant changes in gene expression. We didn't observe a correlation between exosomal mRNA and changes in target cell mRNA or proteins. Instead transferred miRNA significantly affected target cell mRNA translation as demonstrated for selected, most abundant ASML exosomal miRNA besides others, miR-494 known target MAL (myelin and lymphocytes protein)/cadherin17, and miR-542-3p which targets TRAF/cadherin17. Furthermore, MMP transcription suggested to accompany cadherin17 dwon-regulation was upregulated in miR-494 or miR542-3p transfected or exosome co-cultured LnStr. Taken together, tumor exosomes target in vivo non-transformed cells in premetastatic organs. Exosome uptake induced altered target celll gene expression is strongly promoted by exosomal miRNA where we demonstrate for the first time that exosomes/exosomal miRNA from a metastasizing tumor line can modulate stroma cells from premetastatic organs. Endothelial cells lines were treated with pancreatic adenocarcinoma (AS) derived exosomes or pancreatic adenocarcinoma derived exosomes expressing tetraspanin 8. Total RNA was isolated and used to perform the Agilent gene expression microarrays. In this assay a replicate of endothelial cell lines treated with ASTspan8 were also included. Moreover, total RNA from both base line expression of endothelial cells and rat endothelial fibroblasts were also used to perfrom gene expression microarrays. RNA isolated from Rat endothelial fibroblasts treated with the exosomes derived from rat pancreatic adenocarcinoma and exosomes derived from rat pancreatic adenocarcinoma expressing tetraspanin8 were individually used to perfrom gene expression microarrays. RNA isolated from exosomes derived from rat pancreatic adenocarcinoma cell lines expressing tetraspanin were used to peform gene expresiion to see the base line expression. Another replicate were also used. RNA isolated from base line or control of rat pancreatic adenocarcinoma wild type cells and also base line RNA isolated from rat pancreatic adenocarcinoma cells lines where CD44 was knock-down.

Dataset Information

Tissue- and plasma-derived exosomal protein biomarkers define multiple human cancers

Publications

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers.

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