Hartman Institute for Therapeutic Organ Regeneration

Endothelial cell-leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities.

TitleEndothelial cell-leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities.
Publication TypeJournal Article
Year of Publication2023
AuthorsCappelli LVincenzo, Fiore D, Phillip JM, Yoffe L, Di Giacomo F, Chiu W, Hu Y, Kayembe C, Ginsberg M, Consolino L, Durán JGabriel Ba, Zamponi N, Melnick AM, Boccalatte F, Tam W, Elemento O, Chiaretti S, Guarini A, Foà R, Cerchietti L, Rafii S, Inghirami G
Date Published2023 Feb 02
KeywordsCell Communication, Coculture Techniques, Endothelial Cells, Humans, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Tumor Microenvironment

<p>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.</p>

Alternate JournalBlood
PubMed ID35981563
PubMed Central IDPMC10082359
Grant ListP01 CA229086 / CA / NCI NIH HHS / United States
P01 CA229100 / CA / NCI NIH HHS / United States
R35 HL150809 / HL / NHLBI NIH HHS / United States
RC2 DK114777 / DK / NIDDK NIH HHS / United States
U01 AI138329 / AI / NIAID NIH HHS / United States

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
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