Targeting P-selectin blocks neuroblastoma growth
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Riitta Nolo1,*, Shelley Herbrich1,*, Arvind Rao3, Patrick Zweidler-McKay1,6 Sankaranarayanan Kannan1,* and Vidya Gopalakrishnan1,2,4,5
1Departments of Pediatrics, M.D. Anderson Cancer Center, Houston, TX, USA
2Molecular and Cellular Oncology, M.D. Anderson Cancer Center, Houston, TX, USA
3Bioinformatics and Computational Biology, M.D. Anderson Cancer Center, Houston, TX, USA
4Center for Cancer Epigenetics, M.D. Anderson Cancer Center, Houston, TX, USA
5Brain Tumor Center, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
6ImmunoGen Inc., Waltham, MA, USA
*These authors have contributed equally to this work
Vidya Gopalakrishnan, email: [email protected]
Sankaranarayanan Kannan, email: [email protected]
Keywords: neuroblastoma, P-selectin, selectin inhibition, CyTOF, tumor heterogeneity
Received: May 23, 2017 Accepted: August 28, 2017 Published: September 28, 2017
Selectins and their ligands have been implicated in tumor growth and progression in carcinomas, but their role in neuroblastoma has not been systematically examined. In the current study we evaluated L-, P- and E-selectin binding to neuroblastoma cells and the expression of some of their known ligands, namely CD44, CD24 and P-selectin glycoprotein ligand-1 (PSGL-1). Genetic loss of PSGL-1 or CD24 and pharmacological inhibition of P-selectin reduced P-selectin binding to neuroblastoma cells in vitro. Targeting P-selectin using specific antibodies promoted a significant reduction in the growth of neuroblastoma tumors in vivo. In mechanistic studies binding of P-selectin to neuroblastoma cells activated Src and several other pro-survival kinases such as ERK1, AKT, FAK and p38. Interestingly, comparative mass single cell cytometry (CyTOF) analyses revealed considerable intra- and inter-cell line heterogeneity with respect to response to P-selectin binding. Additionally, the downstream response to all selectins showed general similarity. Our findings reported here not only provide pre-clinical evidence in support of therapeutic targeting of P-selectin, but also highlight the heterogeneity in response of tumor cells to P-selectin binding. These observations provide the basis for combining P-selectin inhibition with other targeted therapies for neuroblastoma.
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