Browsing by Subject "Insulin-like growth factor 1 receptor (IGF-1R)"

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Myeloid cells provide critical support for T-ALL in vivo
(2021-01-22) Lyu, Aram; Ehrlich, Lauren; Brock, Amy; Digiovanni, John; Georgiou, George; Iyer, Vishwanath
Despite harboring mutations in oncogenes and tumor suppressors that promote tumor growth, T-cell acute lymphoblastic leukemia (T-ALL) cells require exogenous cell types or signals to survive in culture. We previously reported that myeloid cells, particularly dendritic cells, from the thymic tumor microenvironment support the survival and proliferation of primary mouse T-ALL cells in vitro. This dissertation seeks to address two gaps in knowledge in our field. First, it remains to be determined whether tumor-associated myeloid cells promote T-ALL progression in vivo. Second, if so, the molecular mechanisms underlying myeloid-mediated support of T-ALL remain unknown. In this dissertation, I provide evidence that tumor-associated myeloid cells provide critical support for T-ALL both in mouse models and in patients. First, in vivo depletion of myeloid cells using pharmacologic or genetic means results in a significant reduction in T-ALL burden in multiple organs in two independent mouse models of T-ALL and prolongs survival. Consistent with mouse models, myeloid cells derived from human peripheral blood monocytes support survival of primary patient T-ALL cells in vitro. Furthermore, enriched macrophage gene signatures in published clinical samples correlate with worse outcomes for pediatric T-ALL patients. These results indicate that tumor-associated myeloid cells promote T-ALL pathogenesis in vivo. Second, transcriptional profiling and functional assays identify activation of IGF1R and integrin signaling as critical components of myeloid-mediated T-ALL support. Consistent with this, acute in vivo myeloid ablation significantly diminishes IGF1R activation in T-ALL cells. In addition, in vivo blockade of integrin-mediated cell adhesion in leukemic mice results in a significant reduction in T-ALL burden. Moreover, enrichment of integrin signaling is associated with elevated myeloid gene signatures and inferior outcomes in pediatric T-ALL patients. These results suggest that IGF1R and integrin signaling plays a critical role in myeloid-mediated T-ALL support. Collectively, the research presented in this dissertation demonstrates that tumor-associated myeloid cells provide signals critical for T-ALL progression in multiple organs in vivo and implicates tumor-associated myeloid cells and associated signals as potential therapeutic targets.