Environment-Mediated Drug Resistance in Neuroblastoma.

摘要

During the second year of funding, collaborative experiments have demonstrated that monocytes collaborate with MSC in inducing STAT3-dependent drug resistance in neuroblastoma. Further collaborative work with Dr. Seeger on the cooperation between MSC and monocytes indicate that in vivo, MSC enhance monocyte survival in tumors and increase the growth of neuroblastoma cells. Thus our data so far emphasize the important contribution of MSC and monocytes in neuroblastoma progression (Task 1). We show that S1P/S1PR1 contributes to a sustainable STAT3 activation leading toward increased survival (Task 2), and that Jak2 deletion/inhibition prevents drug resistance (Task 3). Experiments aimed at examining the effect of small pathway inhibitors suggest that inhibition of Jak2, MEK and S1PR1 all contribute to prevent drug resistance, but that inhibition of multiple pathways may be required (Task 4). Experiments aimed at examining the role of IL-6 clearly demonstrate that although IL-6 is involved in STAT3-mediated drug resistance, it is not necessary as STAT3 is activated in IL-6 KO mice and tumors develop in IL-6 KO mice crossed with NB-Tag mice (Task 5). As a result, Task 6 which focused on targeting IL-6 has been abandoned. Task 7 has now been initiated using a combination of S1PR1 and Jak2 inhibitors in vitro and in vivo.