{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:18:37Z","timestamp":1793395117400,"version":"4.5.0"},"reference-count":53,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"756","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,7,17]]},"abstract":"<jats:p>Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence of PNI. Furthermore, CAF-derived extracellular vesicles (EVs) were involved in PNI in dorsal root ganglion coculture and mouse sciatic nerve models. Next, we demonstrated that CAFs promoted PNI through extracellular vesicle transmission of PNI-associated transcript (PIAT). Mechanistically, PIAT specifically bound to YBX1 and blocked the YBX1-Nedd4l interaction to inhibit YBX1 ubiquitination and degradation. Furthermore, PIAT enhanced the binding of YBX1 and PNI-associated mRNAs in a 5-methylcytosine (m5C)\u2013dependent manner. Mutation of m5C recognition motifs in YBX1 or m5C sites in downstream target genes reversed PIAT-mediated PNI. Consistent with these findings, analyses using a KPC mouse model demonstrated that the PIAT\/YBX1 axis enhanced PNI through m5C modification. Clinical data suggested that the PIAT expression in the serum EVs of patients with pancreatic cancer was associated with the degree of neural invasion and prognosis. Our study revealed the important role of the PIAT\/YBX1 signaling axis in the tumor microenvironment (TME) in promoting tumor cell PNI and provided a new target for precise interference with CAFs and RNA methylation in the TME to suppress PNI in pancreatic cancer.<\/jats:p>","DOI":"10.1126\/scitranslmed.adi0178","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T14:00:49Z","timestamp":1721224849000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":67,"title":["Extracellular vesicle\u2013packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0528-9014","authenticated-orcid":true,"given":"Shangyou","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4233-0702","authenticated-orcid":true,"given":"Chonghui","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4889-443X","authenticated-orcid":true,"given":"Qing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5773-7174","authenticated-orcid":true,"given":"Tingting","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7047-6499","authenticated-orcid":true,"given":"Guolin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary, Pancreatic and Splenic Surgery, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7144-1933","authenticated-orcid":true,"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."},{"name":"Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuancheng","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."},{"name":"Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rihua","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."},{"name":"Shantou University Medical College, Shantou, Guangdong 515041, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9924-9054","authenticated-orcid":true,"given":"Changhao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3990-0308","authenticated-orcid":true,"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7422-5222","authenticated-orcid":true,"given":"Rufu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, People\u2019s Republic of China."},{"name":"Department of Hepatobiliary, Pancreatic and Splenic Surgery, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, People\u2019s Republic of China."},{"name":"Guangdong Cardiovascular Institute, Guangdong Provincial People\u2019s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21708"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12399"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000000968"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000004464"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-2050"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00596-9"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0238-1"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2790"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39104"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.06.017"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau6977"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-013-1020-6"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI87734"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00988-x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.25541"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.1639"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0361-y"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.06.033"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00920-x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.900155"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.038361"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12948"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0036-9"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI157644"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-020-02648-7"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02253-6"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.24281"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-02198-w"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162024"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0710"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0094"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0644"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2020.05.004"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40314-w"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-021-01978-0"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-022-10336-8"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201489282"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.307674"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02325-7"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1049435"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-0991"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-022-00857-4"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-01475-w"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-023-02931-z"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.103195"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1334-5"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06038-x"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780080504"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0258(20010130)20:2<237::AID-SIM654>3.0.CO;2-I"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-011-0399-5"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-2689"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.05.065"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-02237-6"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adi0178","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T14:01:11Z","timestamp":1721224871000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adi0178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,17]]},"references-count":53,"journal-issue":{"issue":"756","published-print":{"date-parts":[[2024,7,17]]}},"alternative-id":["10.1126\/scitranslmed.adi0178"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adi0178","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,17]]},"assertion":[{"value":"2023-03-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-06","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadi0178"}}