Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer

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 aggressi...

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Autores: 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.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/188955
Acceso en línea:https://hdl.handle.net/2445/188955
Access Level:acceso abierto
Palabra clave:Càncer
Gastroenterologia
Citocines
Cancer
Gastroenterology
Cytokines
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network_acronym_str ES
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repository_id_str
spelling Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancerKrebs, NiklasKlein, LukasWegwitz, FlorianEspinet, ElisaMaurer, Hans CarloTu, MengyuPenz, FrederikeKüffer, StefanXu, XingboBohnenberger, HanibalCameron, SilkeBrunner, MariusNeesse, AlbrechtKishore, UdayHessmann, ElisabethTrumpp, AndreasStröbel, PhilippBrekken, Rolf A.Ellenrieder, VolkerSingh, Shiv K.CàncerGastroenterologiaCitocinesCancerGastroenterologyCytokinesMetastatic 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.American Society for Clinical Investigation2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/188955Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1172/jci.insight.154475JCI Insight, 2022https://doi.org/10.1172/jci.insight.154475cc by (c) Krebs, Niklas et al., 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1889552026-05-27T06:46:51Z
dc.title.none.fl_str_mv Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer
title Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer
spellingShingle Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer
Krebs, Niklas
Càncer
Gastroenterologia
Citocines
Cancer
Gastroenterology
Cytokines
title_short Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer
title_full Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer
title_fullStr Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer
title_full_unstemmed Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer
title_sort Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer
dc.creator.none.fl_str_mv 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.
author Krebs, Niklas
author_facet 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.
author_role author
author2 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.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer
Gastroenterologia
Citocines
Cancer
Gastroenterology
Cytokines
topic Càncer
Gastroenterologia
Citocines
Cancer
Gastroenterology
Cytokines
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/188955
url https://hdl.handle.net/2445/188955
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.154475
JCI Insight, 2022
https://doi.org/10.1172/jci.insight.154475
dc.rights.none.fl_str_mv cc by (c) Krebs, Niklas et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Krebs, Niklas et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869419772740894720
score 15,301603

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