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Title: | Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer |
Author: | Krebs, Niklas Klein, Lukas Wegwitz, Florian Espinet, Elisa Maurer, Hans Carlo Tu, Mengyu Penz, Frederike Küffer, Stefan Xu, Xingbo Bohnenberger, Hanibal Cameron, Silke Brunner, Marius Neesse, Albrecht Kishore, Uday Hessmann, Elisabeth Trumpp, Andreas Ströbel, Philipp Brekken, Rolf A. Ellenrieder, Volker Singh, Shiv K. |
Keywords: | Càncer Gastroenterologia Citocines Cancer Gastroenterology Cytokines |
Issue Date: | 22-Aug-2022 |
Publisher: | American Society for Clinical Investigation |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.154475 |
It is part of: | JCI Insight, 2022 |
URI: | http://hdl.handle.net/2445/188955 |
Related resource: | https://doi.org/10.1172/jci.insight.154475 |
ISSN: | 2379-3708 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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