TY - JOUR
T1 - Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation
AU - Triplett, Todd A.
AU - Cardenas, Kim T.
AU - Lancaster, Jessica N.
AU - Hu, Zicheng
AU - Selden, Hilary J.
AU - Jasso, Guadalupe J.
AU - Balasubramanyam, Sadhana
AU - Chan, Kathy
AU - Li, Liqi
AU - Chen, Xi
AU - Marcogliese, Andrea N.
AU - Davé, Utpal P.
AU - Love, Paul E.
AU - Ehrlich, Lauren I.R.
N1 - Funding Information:
We thank Coby Tran for assistance with immunostaining, Ellen R. Richie for helpful discussions, and Michele Redell for her advice and expertise in human hematologic malignancies. We also thank the staff at The University of Texas at Austin Animal Facilities. This work was supported by Recruitment Award R1003 from the Cancer Prevention and Research Institute of Texas (to L.I.R.E.) and by the Intramural Research Program of the NIH (PEL: Project number: 1ZIAHD001803-22). T.A.T. was supported by Postdoctoral Fellowship PF-14-216-01-TBG from the American Cancer Society.
PY - 2016/2/23
Y1 - 2016/2/23
N2 - Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth,we first performed gene expression profiling,which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DCmediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.
AB - Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth,we first performed gene expression profiling,which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DCmediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.
KW - Dendritic cell
KW - IGF1R
KW - Leukemia
KW - T-ALL
KW - Tumor microenvironment
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U2 - 10.1073/pnas.1520245113
DO - 10.1073/pnas.1520245113
M3 - Article
C2 - 26862168
AN - SCOPUS:84959221997
SN - 0027-8424
VL - 113
SP - E1016-E1025
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
ER -