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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Detalhes bibliográficos
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 documento: artigo
Estado:Versão publicada
Data de publicação:2022
País:España
Recursos:Universidad de Barcelona
Repositório:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/188955
Acesso em linha:https://hdl.handle.net/2445/188955
Access Level:Acceso aberto
Palavra-chave:Càncer
Gastroenterologia
Citocines
Cancer
Gastroenterology
Cytokines
Descrição
Resumo: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.

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