{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:54:20Z","timestamp":1785772460815,"version":"3.56.0"},"reference-count":67,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["101021078"],"award-info":[{"award-number":["101021078"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["PLASTICAN\u2010101021078"],"award-info":[{"award-number":["PLASTICAN\u2010101021078"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["540805631\u2010TP01"],"award-info":[{"award-number":["540805631\u2010TP01"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["540805631\u2010TP17"],"award-info":[{"award-number":["540805631\u2010TP17"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["540805631\u2010TP17"],"award-info":[{"award-number":["540805631\u2010TP17"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["540805631\u2010TP01"],"award-info":[{"award-number":["540805631\u2010TP01"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["318346496\u2010TP16"],"award-info":[{"award-number":["318346496\u2010TP16"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["441891347\u2010P02"],"award-info":[{"award-number":["441891347\u2010P02"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GRK2336"],"award-info":[{"award-number":["GRK2336"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2023_EKEA.112"],"award-info":[{"award-number":["2023_EKEA.112"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Recently, we suggested the combination of chemotherapy and P2RX4 inhibition as a promising novel therapeutic approach for P2RX4\u2010expressing epithelial tumors to prevent paracrine resistance. Here, we aimed to assess whether determining\n                    <jats:italic>P2RX4<\/jats:italic>\n                    expression status in colorectal and pancreatic cancer patients would allow stratification of potentially responsive patients. Therefore,\n                    <jats:italic>P2RX4<\/jats:italic>\n                    expression levels were determined by RNA sequencing and immunohistochemistry. Subcellular localization of P2RX4 isoforms was analyzed in HeLa cells and patient\u2010derived tumor organoids. In contrast to its RNA expression profile, P2RX4 protein levels exhibited differential regulation in human colorectal and pancreatic cancer epithelia due to alternative splicing. Interpatient heterogeneity was greater in colorectal cancer than in pancreatic cancer. Notably, these variations in expression did not correlate with overall patient survival. Alternative\n                    <jats:italic>P2RX4<\/jats:italic>\n                    transcripts gave rise to functionally distinct protein isoforms that differed in subcellular localization and total protein abundance. Only the correctly spliced, canonical P2RX4 isoform was localized to the plasma membrane and was capable of mediating downstream signaling. Accordingly, P2RX4 inhibition in combination with chemotherapy was effective exclusively in patient\u2010derived tumor organoids expressing the canonical\n                    <jats:italic>P2RX4<\/jats:italic>\n                    transcript. In summary, immunohistochemical, but not transcriptomic, assessment of P2RX4 expression enabled the prediction of sensitivity to combinatorial treatment and facilitated the identification of patients who may benefit from P2RX4 inhibition during chemotherapy. Given the lower degree of heterogeneity observed in pancreatic cancer, this tumor entity may represent a promising candidate for early\u2010phase clinical evaluation of chemotherapy combined with P2RX4 inhibition. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70082","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:28:21Z","timestamp":1780471701000},"page":"55-68","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aberrant alternative splicing of purinergic receptor\n                    <scp>P2RX4<\/scp>\n                    prevents sensitivity towards combinatorial treatment in colorectal and pancreatic cancer"],"prefix":"10.1002","volume":"270","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6991-9910","authenticated-orcid":false,"given":"Christoph","family":"Steup","sequence":"first","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"},{"name":"Goethe University Frankfurt, Department of Medicine I University Hospital Frankfurt  Frankfurt am Main Germany"},{"name":"Frankfurt Cancer Institute, Goethe University Frankfurt  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4961-9483","authenticated-orcid":false,"given":"Julian","family":"Dosch","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4839-5596","authenticated-orcid":false,"given":"Christopher","family":"Dietz\u2010Fricke","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"},{"name":"Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Khosraviseftejani","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Engel","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9059-3273","authenticated-orcid":false,"given":"Adalbert F de","family":"Valk","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5611-1629","authenticated-orcid":false,"given":"Dominic","family":"Menger","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Welker","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Dr. Senckenberg Institutes of Pathology and Human Genetics (SPH), University Frankfurt, University Hospital Frankfurt  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1017-3744","authenticated-orcid":false,"given":"Peter J","family":"Wild","sequence":"additional","affiliation":[{"name":"Frankfurt Cancer Institute, Goethe University Frankfurt  Frankfurt am Main Germany"},{"name":"Goethe University Frankfurt, Dr. Senckenberg Institutes of Pathology and Human Genetics (SPH), University Frankfurt, University Hospital Frankfurt  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7375-1249","authenticated-orcid":false,"given":"Kilian B","family":"Kennel","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Kantlehner","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7703-7747","authenticated-orcid":false,"given":"Paul K","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Frankfurt Cancer Institute, Goethe University Frankfurt  Frankfurt am Main Germany"},{"name":"Goethe University Frankfurt, Dr. Senckenberg Institutes of Pathology and Human Genetics (SPH), University Frankfurt, University Hospital Frankfurt  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3928-6080","authenticated-orcid":false,"given":"Florian R","family":"Greten","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"},{"name":"Frankfurt Cancer Institute, Goethe University Frankfurt  Frankfurt am Main Germany"},{"name":"German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00302-4"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3599"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers6031769"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.027"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.432"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2023"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.07.026"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2620"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.215"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10690"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05426-1"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08198"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.1.H285"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201409071"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13734"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2015.04.014"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00558.2009"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00191"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.108110"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep32461"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-011-9288-x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.010348"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201411169"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-021-01352-9"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.4"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120972"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9112511"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5815"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-04069-w"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-023-02713-1"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13081234"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2764"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-16747-x"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-04461-6"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-0050"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1049"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1114"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307202110"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.11.007"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-314353"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-317706"},{"key":"e_1_2_8_44_1","unstructured":"KassambaraA BiecekP.survminer: Drawing Survival Curves using \u2018ggplot2\u2019. R package version 0.5.0 Available from:https:\/\/rpkgs.datanovia.com\/survminer\/index.html."},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-95247-9"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(97)00647-1"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt765"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-00540-4"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161720"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07509"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.09.001"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.457207"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2024.10.010"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.07.001"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1892"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-022-00541-7"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2674"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109016"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.09.053"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1618-0"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10004"},{"key":"e_1_2_8_63_1","unstructured":"GeneCards: P2RX4 Gene \u2010 Purinergic Receptor P2X 4.Weizmann Institute of Science [Accessed 3 March 2025]. Available from:https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=P2RX4."},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112097200"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204844200"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2018.e01055"},{"key":"e_1_2_8_67_1","unstructured":"KorotkevichG SukhovV BudinN et al.Fast gene set enrichment analysis.bioRxiv2016; 060012. [Not peer reviewed]."},{"key":"e_1_2_8_68_1","first-page":"30","article-title":"Site\u2010specific protein labeling with SNAP\u2010tags","volume":"73","author":"Cole NB","year":"2013","journal-title":"Curr Protoc Protein Sci"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.70082","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.70082","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.70082","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:05:29Z","timestamp":1785769529000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.70082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":67,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/path.70082"],"URL":"https:\/\/doi.org\/10.1002\/path.70082","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]},"assertion":[{"value":"2025-11-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}