During the past three funding years, collaborative experiments have demonstrated that monocytes collaborate with MSC in inducing STAT3-dependent drug resistance in neuroblastoma Task 1, that S1PS1PR1 contributes to a sustainable STAT3 activation leading toward increased survival Task 2, and that Jak2 deletioninhibition 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. We show in vitro and in neuroblastoma human xenograft models that treatment with FTY720, an antagonist of S1PR1, dramatically sensitizes drug-resistant neuroblastoma cells to etoposide, indicating that S1PR1 is a critical target for reducing both EMDR and acquired chemo-resistance Task 7.