TY - JOUR
T1 - Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXLassociated inflammatory network in pancreatic cancer
AU - Krebs, Niklas
AU - Klein, Lukas
AU - Wegwitz, Florian
AU - Espinet, Elisa
AU - Maurer, Hans Carlo
AU - Tu, Mengyu
AU - Penz, Frederike
AU - Küffer, Stefan
AU - Xu, Xingbo
AU - Bohnenberger, Hanibal
AU - Cameron, Silke
AU - Brunner, Marius
AU - Neesse, Albrecht
AU - Kishore, Uday
AU - Hessmann, Elisabeth
AU - Trumpp, Andreas
AU - Ströbel, Philipp
AU - Brekken, Rolf A.
AU - Ellenrieder, Volker
AU - Singh, Shiv K.
N1 - Publisher Copyright:
© 2022, Krebs et al.
PY - 2022/8/22
Y1 - 2022/8/22
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.154475
DO - 10.1172/jci.insight.154475
M3 - Article
C2 - 35993361
AN - SCOPUS:85136267652
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 16
M1 - e154475
ER -