{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:44:52Z","timestamp":1790844292737,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HA2432\/5-2"],"award-info":[{"award-number":["HA2432\/5-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>In chronic lymphocytic leukemia (CLL), the tumor cells receive survival support from stromal cells through direct cell contact, soluble factors and extracellular vesicles (EVs). The protein tyrosine kinase Lyn is aberrantly expressed in the malignant and stromal cells in CLL tissue. We studied the role of Lyn in the EV-based communication and tumor support.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We compared the Lyn-dependent EV release, uptake and functionality using Lyn-proficient (wild-type) and -deficient stromal cells and primary CLL cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lyn-proficient cells caused a significantly higher EV release and EV uptake as compared to Lyn-deficient cells and also conferred stronger support of primary CLL cells. Proteomic comparison of the EVs from Lyn-proficient and -deficient stromal cells revealed 70 significantly differentially expressed proteins. Gene ontology studies categorized many of which to organization of the extracellular matrix, such as collagen, fibronectin, fibrillin, Lysyl oxidase like 2, integrins and endosialin (CD248). In terms of function, a knockdown of CD248 in Lyn<jats:sup>+<\/jats:sup> HS-5 cells resulted in a diminished B-CLL cell feeding capacity compared to wildtype or scrambled control cells. CD248 is a marker of certain tumors and cancer-associated fibroblast (CAF) and crosslinks fibronectin and collagen in a membrane-associated context.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data provide preclinical evidence that the tyrosine kinase Lyn crucially influences the EV-based communication between stromal and primary B-CLL cells by raising EV release and altering the concentration of functional molecules of the extracellular matrix.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2022.1059028","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T04:37:52Z","timestamp":1673584672000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Stromal cells support the survival of human primary chronic lymphocytic leukemia (CLL) cells through Lyn-driven extracellular vesicles"],"prefix":"10.3389","volume":"9","author":[{"given":"Tha\u00eds Dolzany","family":"de Oliveira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"vom Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio","family":"Rebollido-Rios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liudmila","family":"Lobastova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Lettau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ottmar","family":"Janssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prerana","family":"Wagle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong-Hien","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hallek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hinrich P.","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1046\/j.1365-2141.2003.04679.x","article-title":"Role of the microenvironment in chronic lymphocytic leukaemia.","volume":"123","author":"Caligaris-Cappio","year":"2003","journal-title":"Br J Haematol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.semcancer.2013.08.011","article-title":"The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies.","volume":"24","author":"Burger","year":"2014","journal-title":"Semin Cancer Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1146\/annurev-cellbio-101512-122326","article-title":"Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles.","volume":"30","author":"Colombo","year":"2014","journal-title":"Annu Rev Cell Dev Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e12140","DOI":"10.1002\/jev2.12140","article-title":"Formation of a protein corona on the surface of extracellular vesicles in blood plasma.","volume":"10","author":"Toth","year":"2021","journal-title":"J Extracell Vesicles."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.3324\/haematol.2016.163337","article-title":"Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications.","volume":"102","author":"Crompot","year":"2017","journal-title":"Haematologica."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1182\/blood-2014-12-618025","article-title":"Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.","volume":"126","author":"Paggetti","year":"2015","journal-title":"Blood."},{"key":"B7","doi-asserted-by":"publisher","first-page":"784691","DOI":"10.3389\/fimmu.2021.784691","article-title":"Bone marrow lymphoid niche adaptation to mature B cell neoplasms.","volume":"12","author":"Dumontet","year":"2021","journal-title":"Front Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"6249","DOI":"10.3390\/ijms23116249","article-title":"Lysyl oxidase family enzymes and their role in tumor progression.","volume":"23","author":"Liburkin-Dan","year":"2022","journal-title":"Int J Mol Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1021\/pr200682z","article-title":"Proteomic analysis of microvesicles derived from human mesenchymal stem cells.","volume":"11","author":"Kim","year":"2012","journal-title":"J Proteome Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3299","DOI":"10.1111\/febs.14985","article-title":"C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation.","volume":"286","author":"Khan","year":"2019","journal-title":"FEBS J."},{"key":"B11","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.devcel.2020.05.031","article-title":"Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2\/LYN complex.","volume":"54","author":"Fattet","year":"2020","journal-title":"Dev Cell."},{"key":"B12","doi-asserted-by":"publisher","first-page":"eabg3449","DOI":"10.1126\/scisignal.abg3449","article-title":"Fibrous stroma: driver and passenger in cancer development.","volume":"15","author":"Sharma","year":"2022","journal-title":"Sci Signal."},{"key":"B13","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1038\/onc.2016.253","article-title":"Extracellular vesicles swarm the cancer microenvironment: from tumor-stroma communication to drug intervention.","volume":"36","author":"Wendler","year":"2017","journal-title":"Oncogene."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3297","DOI":"10.1182\/blood-2014-12-618470","article-title":"Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling.","volume":"125","author":"Yeh","year":"2015","journal-title":"Blood."},{"key":"B15","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.ccell.2016.09.007","article-title":"LYN kinase in the tumor microenvironment is essential for the progression of chronic lymphocytic leukemia.","volume":"30","author":"Nguyen","year":"2016","journal-title":"Cancer Cell."},{"key":"B16","doi-asserted-by":"publisher","first-page":"25466","DOI":"10.1074\/jbc.M112.364562","article-title":"The actin regulatory protein HS1 interacts with Arp2\/3 and mediates efficient neutrophil chemotaxis.","volume":"287","author":"Cavnar","year":"2012","journal-title":"J Biol Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1146\/annurev-immunol-020711-075027","article-title":"Pathogenesis of human B cell lymphomas.","volume":"30","author":"Shaffer","year":"2012","journal-title":"Annu Rev Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1182\/blood-2012-09-457119","article-title":"Targeting the LYN\/HS1 signaling axis in chronic lymphocytic leukemia.","volume":"121","author":"ten Hacken","year":"2013","journal-title":"Blood."},{"key":"B19","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1007\/978-1-4939-9686-5_16","article-title":"Filopodia quantification using FiloQuant.","volume":"2040","author":"Jacquemet","year":"2019","journal-title":"Methods Mol Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/nprot.2017.147","article-title":"Proteome-wide identification of ubiquitin interactions using UbIA-MS.","volume":"13","author":"Zhang","year":"2018","journal-title":"Nat Protoc."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies.","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters.","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS."},{"key":"B23","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1093\/bioinformatics\/btr645","article-title":"MSnbase-an R\/Bioconductor package for isobaric tagged mass spectrometry data visualization, processing and quantitation.","volume":"28","author":"Gatto","year":"2012","journal-title":"Bioinformatics."},{"key":"B24","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1039\/c5mb00663e","article-title":"ReactomePA: an R\/Bioconductor package for reactome pathway analysis and visualization.","volume":"12","author":"Yu","year":"2016","journal-title":"Mol Biosyst."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3265","DOI":"10.1038\/s41598-019-39882-z","article-title":"Src in endosomal membranes promotes exosome secretion and tumor progression.","volume":"9","author":"Hikita","year":"2019","journal-title":"Sci Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nrm2406","article-title":"Filopodia: molecular architecture and cellular functions.","volume":"9","author":"Mattila","year":"2008","journal-title":"Nat Rev Mol Cell Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1083\/jcb.201506084","article-title":"Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER.","volume":"213","author":"Heusermann","year":"2016","journal-title":"J Cell Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.cub.2018.11.053","article-title":"Filopodome mapping identifies p130Cas as a mechanosensitive regulator of filopodia stability.","volume":"29","author":"Jacquemet","year":"2019","journal-title":"Curr Biol."},{"key":"B29","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1182\/blood.V100.5.1795.h81702001795_1795_1801","article-title":"Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1.","volume":"100","author":"Pedersen","year":"2002","journal-title":"Blood."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e100","DOI":"10.3324\/haematol.2016.153197","article-title":"Extracellular vesicles released from chronic lymphocytic leukemia cells exhibit a disease relevant mRNA signature and transfer mRNA to bystander cells.","volume":"102","author":"Reiners","year":"2017","journal-title":"Haematologica."},{"key":"B31","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/s41375-018-0366-8","article-title":"New roles for B cell receptor associated kinases: when the B cell is not the target.","volume":"33","author":"Nguyen","year":"2019","journal-title":"Leukemia."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1038\/srep01658","article-title":"The role of filopodia in the recognition of nanotopographies.","volume":"3","author":"Albuschies","year":"2013","journal-title":"Sci Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.cellsig.2014.11.025","article-title":"Effect of Cdc42 domains on filopodia sensing, cell orientation, and haptotaxis.","volume":"27","author":"Amarachintha","year":"2015","journal-title":"Cell Signal."},{"key":"B34","doi-asserted-by":"publisher","first-page":"7408","DOI":"10.1074\/jbc.M009604200","article-title":"Molecular cloning and characterization of endosialin, a C-type lectin-like cell surface receptor of tumor endothelium.","volume":"276","author":"Christian","year":"2001","journal-title":"J Biol Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3810","DOI":"10.3390\/cancers14153810","article-title":"Cancer-associated fibroblasts in a 3D engineered tissue model induce tumor-like matrix stiffening and EMT transition.","volume":"14","author":"Millet","year":"2022","journal-title":"Cancers (Basel)."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.3389\/fonc.2020.01422","article-title":"Importance of crosstalk between chronic lymphocytic leukemia cells and the stromal microenvironment: direct contact, soluble factors, and extracellular vesicles.","volume":"10","author":"Dubois","year":"2020","journal-title":"Front Oncol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.1059028\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T04:37:55Z","timestamp":1673584675000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.1059028\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,13]]},"references-count":36,"alternative-id":["10.3389\/fmed.2022.1059028"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.1059028","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,13]]},"article-number":"1059028"}}