TY - JOUR
T1 - Endothelial cell–leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities
AU - Cappelli, Luca Vincenzo
AU - Fiore, Danilo
AU - Phillip, Jude M.
AU - Yoffe, Liron
AU - Di Giacomo, Filomena
AU - Chiu, William
AU - Hu, Yang
AU - Kayembe, Clarisse
AU - Ginsberg, Michael
AU - Consolino, Lorena
AU - Barcia Duran, Jose Gabriel
AU - Zamponi, Nahuel
AU - Melnick, Ari M.
AU - Boccalatte, Francesco
AU - Tam, Wayne
AU - Elemento, Olivier
AU - Chiaretti, Sabina
AU - Guarini, Anna
AU - Foà, Robin
AU - Cerchietti, Leandro
AU - Rafii, Shahin
AU - Inghirami, Giorgio
N1 - Funding Information:
The authors thank J. Casano and A. Miyaguchi for technical support, and A. Arkur and S. B. Shah for administrative assistance. The authors are grateful to the Weill Cornell Medical College Epigenomics Core Facility for next-generation sequencing (NGS) library preparation and sequencing for this study. The authors also thank the members of the Weill Cornell Flow Cytometry Core Facility and Sandra and Edward Meyer Cancer Center PDX shared resource. This work was supported in part by the Italian Association for Cancer Research (AIRC, Milan, Italy), Metastases 5×1000 Special Program, and grant 21198 (R.F.); National Institutes of Health (NIH), National Cancer Institute (NCI) grants CA229086, CA229100, Leukemia and Lymphoma Society grant LLS 7011-16, departmental funds, and the Sandra and Edward Meyer Cancer Fund (G.I.); and the Rita-Levi Montalcini grant from the Italian Ministry of University and Research (MIUR) (D.F.). J.M.P. is supported by NIH NCI grant R01CA18710903S1. L.V.C. is supported by an American Italian Cancer Foundation (AICF) postdoctoral research fellowship. S.R. is funded by the Hartman Institute for Therapeutic Organ Regeneration; the Ansary Stem Cell Institute; NIH, National Heart, Lung, and Blood Institute grant R35 HL150809, NIH, National Institute of Diabetes and Digestive and Kidney Diseases grant RC2DK114777 and NIH, National Institute of Allergy and Infectious Diseases grant U01AI138329; the Empire State Stem Cell Board (C030160); the Daedalus Fund for Innovation; the Selma and Lawrence Ruben Science to Industry Bridge Fund from Weill Cornell Medicine; and the Starr Foundation stem cell core project and initiatives (TRI-SCI 2019-029). Contribution: L.V.C. D.F. J.M.P. L.Y. F.D.G. L. Cerchietti, S.R. and W.T. were responsible for conceptualization, formal analysis, methodology, writing-original draft, writing-review and editing; Y.H. and C.K. were responsible for formal analysis, methodology, and editing; W.C. was responsible for formal analysis and methodology; M.G. L. Consolino, and N.Z. were responsible for conceptualization, formal analysis, methodology, and editing; J.G.B.D. was responsible for conceptualization, methodology, and editing; F.B. was responsible for conceptualization, methodology, and editing; A.M.M. S.C. A.G. and R.F. were responsible for conceptualization, writing-review and editing; O.E. was responsible for conceptualization, formal analysis, writing-review and editing; and G.I. was responsible for conceptualization, data curation, formal analysis, supervision, methodology, writing-original draft, project administration, writing-review and editing.
Funding Information:
This work was supported in part by the Italian Association for Cancer Research ( AIRC , Milan, Italy), Metastases 5×1000 Special Program, and grant 21198 (R.F.); National Institutes of Health (NIH), National Cancer Institute (NCI) grants CA229086, CA229100, Leukemia and Lymphoma Society grant LLS 7011-16, departmental funds, and the Sandra and Edward Meyer Cancer Fund (G.I.); and the Rita-Levi Montalcini grant from the Italian Ministry of University and Research ( MIUR ) (D.F.). J.M.P. is supported by NIH NCI grant R01CA18710903S1. L.V.C. is supported by an American Italian Cancer Foundation ( AICF ) postdoctoral research fellowship. S.R. is funded by the Hartman Institute for Therapeutic Organ Regeneration; the Ansary Stem Cell Institute; NIH, National Heart, Lung, and Blood Institute grant R35 HL150809, NIH, National Institute of Diabetes and Digestive and Kidney Diseases grant RC2DK114777 and NIH, National Institute of Allergy and Infectious Diseases grant U01AI138329; the Empire State Stem Cell Board (C030160); the Daedalus Fund for Innovation; the Selma and LawrenceRuben Science to Industry Bridge Fund from Weill Cornell Medicine; and the Starr Foundation stem cell core project and initiatives (TRI-SCI 2019-029).
Publisher Copyright:
© 2023 American Society of Hematology
PY - 2023/2/2
Y1 - 2023/2/2
N2 - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.
AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.
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U2 - 10.1182/blood.2022015414
DO - 10.1182/blood.2022015414
M3 - Article
C2 - 35981563
AN - SCOPUS:85146046598
SN - 0006-4971
VL - 141
SP - 503
EP - 518
JO - Blood
JF - Blood
IS - 5
ER -