TY - JOUR
T1 - Targeting P-selectin blocks neuroblastoma growth
AU - Nolo, Riitta
AU - Herbrich, Shelley
AU - Rao, Arvind
AU - Zweidler-McKay, Patrick
AU - Kannan, Sankaranarayanan
AU - Gopalakrishnan, Vidya
N1 - Publisher Copyright:
© Nolo et al.
PY - 2017/10/17
Y1 - 2017/10/17
N2 - 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 preclinical 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.
AB - 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 preclinical 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.
KW - CyTOF
KW - Neuroblastoma
KW - P-selectin
KW - Selectin inhibition
KW - Tumor heterogeneity
UR - http://www.scopus.com/inward/record.url?scp=85031502017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031502017&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.21364
DO - 10.18632/oncotarget.21364
M3 - Article
C2 - 29156825
AN - SCOPUS:85031502017
SN - 1949-2553
VL - 8
SP - 86657
EP - 86670
JO - Oncotarget
JF - Oncotarget
IS - 49
ER -