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Poster display session

5320 - CXCR4 inhibition by ulocuplumab prevents EMT of pNET cells in vitro


10 Sep 2017


Poster display session


Eleonora Pellé


Annals of Oncology (2017) 28 (suppl_5): v142-v157. 10.1093/annonc/mdx368


E. Pellé, M. Cives, D. Quaresmini, D. Lovero, C. Felici, P. Cafforio, R. Palmirotta, F. Silvestris

Author affiliations

  • Azienda Ospedaliero-universitaria Consorziale Policlinico Di Bari, University of Bari Aldo Moro, 70124 - Bari/IT


Abstract 5320


NETs overexpress CXCR4. We have previously shown that stimulation of CXCR4 by its ligand SDF-1 promotes EMT and increases the distant tumor spread of NET cells. Ulocuplumab (Ulo) is a fully human IgG4 mAb designed to inhibit the binding of SDF-1 to CXCR4. We investigated the effects of Ulo in preventing pNET spreading in vitro.


Complement-dependent cytotoxicity (CDC), Ab-dependent cell cytotoxicity (ADCC), Ab-dependent cell phagocytosis (ADCP) and direct Ab-induced apoptosis were investigated using three pNET cell lines (BON1, CM, QGP1) treated with Ulo. Transcriptome profiling was performed by RNAseq following incubation with SDF-1 in the presence or absence of Ulo. Flow cytometry was used to characterize the EMT-related phenotype of NET cells, as well as their expression of immune checkpoints in response to EMT-inducing stimuli. Migration and invasion of pNET cells towards liver and bone fragments was evaluated by transwell assays. The effects of Ulo on the intracellular signaling activated by CXCR4 stimulation were investigated by western-blot (WB), while confocal microscopy assessed the nuclear expression of CXCR4 after high-quality nucleocytoplasmic fractionation.


Ulo failed to induce CDC, ADCC and ADCP in pNET cell lines, in absence of significant direct tumor cell killing. Ligand stimulation of CXCR4 promoted an EMT-like transcriptional shift (upregulation of SNAIL, ZEB1, SMAD2), which was abrogated by Ulo. Treatment with SDF-1 induced cadherin switch, but was unable to alter the membrane expression of immune checkpoints including PD-L1, PD-L2 and CD38. Both in vitro migration and invasion of pNET cells towards liver and bone were significantly suppressed by CXCR4 blockade. Stimulation of CXCR4 induced the phosphorylation of Akt, ERK, and NF-kB, resulting in Vimentin overexpression as well as acquirement of mesenchymal patterns including enhanced spindle index. These effects, inhibited by Ulo, were paralleled by a substantial enrichment of CXCR4 on the nuclear membrane.


Ulo suppresses EMT in pNET cell lines by both disabling the intracellular signaling downstream CXCR4 activation and preventing its nuclear localization. The pathophysiology of nuclear CXCR4 needs to be investigated.

Clinical trial identification

Legal entity responsible for the study

Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy


Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy


All authors have declared no conflicts of interest.

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