Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
14
10
2019
accepted:
20
03
2020
entrez:
5
6
2020
pubmed:
5
6
2020
medline:
5
6
2020
Statut:
epublish
Résumé
Interpreting how multicellular interactions in the tumor affect resistance pathways to BRAF and MEK1/2 MAPK inhibitors (MAPKi) remains a challenge. To investigate this, we profiled global ligand-receptor interactions among tumor and stromal/immune cells from biopsies of MAPK-driven disease. MAPKi increased tumor-associated macrophages (TAMs) in some patients, which correlated with poor clinical response, and MAPKi coamplified bidirectional tumor-TAM signaling via receptor tyrosine kinases (RTKs) including AXL, MERTK, and their ligand GAS6. In xenograft tumors, intravital microscopy simultaneously monitored in situ single-cell activities of multiple kinases downstream of RTKs, revealing MAPKi increased TAMs and enhanced bypass signaling in TAM-proximal tumor cells. As a proof-of-principle strategy to block this signaling, we developed a multi-RTK kinase inhibitor nanoformulation that accumulated in TAMs and delayed disease progression. Thus, bypass signaling can reciprocally amplify across nearby cell types, offering new opportunities for therapeutic design.
Identifiants
pubmed: 32494745
doi: 10.1126/sciadv.aaz8521
pii: aaz8521
pmc: PMC7244320
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
eaaz8521Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM069668
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA079443
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG002295
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA207866
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206890
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA207744
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA096504
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA217377
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA206997
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA112967
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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