Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/188955
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Krebs, Niklas | - |
dc.contributor.author | Klein, Lukas | - |
dc.contributor.author | Wegwitz, Florian | - |
dc.contributor.author | Espinet, Elisa | - |
dc.contributor.author | Maurer, Hans Carlo | - |
dc.contributor.author | Tu, Mengyu | - |
dc.contributor.author | Penz, Frederike | - |
dc.contributor.author | Küffer, Stefan | - |
dc.contributor.author | Xu, Xingbo | - |
dc.contributor.author | Bohnenberger, Hanibal | - |
dc.contributor.author | Cameron, Silke | - |
dc.contributor.author | Brunner, Marius | - |
dc.contributor.author | Neesse, Albrecht | - |
dc.contributor.author | Kishore, Uday | - |
dc.contributor.author | Hessmann, Elisabeth | - |
dc.contributor.author | Trumpp, Andreas | - |
dc.contributor.author | Ströbel, Philipp | - |
dc.contributor.author | Brekken, Rolf A. | - |
dc.contributor.author | Ellenrieder, Volker | - |
dc.contributor.author | Singh, Shiv K. | - |
dc.date.accessioned | 2022-09-12T12:18:39Z | - |
dc.date.available | 2022-09-12T12:18:39Z | - |
dc.date.issued | 2022-08-22 | - |
dc.identifier.issn | 2379-3708 | - |
dc.identifier.uri | http://hdl.handle.net/2445/188955 | - |
dc.description.abstract | Metastatic pancreatic cancer (PDAC) has a poor clinical outcome with a 5-year survival rate below 3%. Recent transcriptome profiling of PDAC biopsies has identified 2 clinically distinct subtypes - the basal-like (BL) subtype with poor prognosis and therapy resistance compared with the less aggressive and drug-susceptible classical (CLA) subtype. However, the mechanistic events and environmental factors that promote the BL subtype identity are not very clear. Using preclinical models, patient-derived xenografts, and FACS-sorted PDAC patient biopsies, we report here that the axon guidance receptor, roundabout guidance receptor 3 (ROB03), promotes the BL metastatic program via a potentially unique AXL/IL-6/phosphorylated STAT3 (p-STAT3) regulatory axis. RNA-Seq identified a R0803-mediated 81-specific gene program, while tyrosine kinase profiling revealed AXL as the key mediator of the p-STAT3 activation. CRISPR/dCas9-based 80803 silencing disrupted the AXL/p-STAT3 signaling axis, thereby halting metastasis and enhancing therapy sensitivity. Transcriptome analysis of resected patient tumors revealed that AXL(hi) neoplastic cells associated with the inflammatory stroma I program. Combining AXL inhibitor and chemotherapy substantially restored a CLA phenotypic state and reduced disease aggressiveness. Thus, we conclude that a 1:101303-driven hierarchical network determines the inflammatory and prometastatic programs in a specific PDAC subtype. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | American Society for Clinical Investigation | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.154475 | - |
dc.relation.ispartof | JCI Insight, 2022 | - |
dc.relation.uri | https://doi.org/10.1172/jci.insight.154475 | - |
dc.rights | cc by (c) Krebs, Niklas et al., 2022 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) | - |
dc.subject.classification | Càncer | - |
dc.subject.classification | Gastroenterologia | - |
dc.subject.classification | Citocines | - |
dc.subject.other | Cancer | - |
dc.subject.other | Gastroenterology | - |
dc.subject.other | Cytokines | - |
dc.title | Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2022-09-08T08:51:39Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 35993361 | - |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
jci.insight.154475.v1.pdf | 6.2 MB | Adobe PDF | View/Open |
This item is licensed under a
Creative Commons License