Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXLassociated inflammatory network in pancreatic cancer

Niklas Krebs, Lukas Klein, Florian Wegwitz, Elisa Espinet, Hans Carlo Maurer, Mengyu Tu, Frederike Penz, Stefan Küffer, Xingbo Xu, Hanibal Bohnenberger, Silke Cameron, Marius Brunner, Albrecht Neesse, Uday Kishore, Elisabeth Hessmann, Andreas Trumpp, Philipp Ströbel, Rolf A. Brekken, Volker Ellenrieder, Shiv K. Singh

Research output: Contribution to journalArticlepeer-review

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 (ROBO3), promotes the BL metastatic program via a potentially unique AXL/IL-6/phosphorylated STAT3 (p-STAT3) regulatory axis. RNA-Seq identified a ROBO3-mediated BL-specific gene program, while tyrosine kinase profiling revealed AXL as the key mediator of the p-STAT3 activation. CRISPR/dCas9-based ROBO3 silencing disrupted the AXL/p-STAT3 signaling axis, thereby halting metastasis and enhancing therapy sensitivity. Transcriptome analysis of resected patient tumors revealed that AXLhi neoplastic cells associated with the inflammatory stromal program. Combining AXL inhibitor and chemotherapy substantially restored a CLA phenotypic state and reduced disease aggressiveness. Thus, we conclude that a ROBO3-driven hierarchical network determines the inflammatory and prometastatic programs in a specific PDAC subtype.

Original languageEnglish (US)
Article numbere154475
JournalJCI Insight
Volume7
Issue number16
DOIs
StatePublished - Aug 22 2022

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXLassociated inflammatory network in pancreatic cancer'. Together they form a unique fingerprint.

Cite this