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Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy
Name
1-s2.0-S2211124720314911-main.pdf
Description
Published version
Size
1.67 MB
Format
Adobe PDF
Checksum (MD5)
82b309f45e164cf6f65467801b9353cd
Author(s)
Wang, Stephanie J
Li, Ran
Ng, Thomas SC
Luthria, Gaurav
Oudin, Madeleine J
Prytyskach, Mark
Kohler, Rainer H
Weissleder, Ralph
Lauffenburger, Douglas A
Miller, Miles A
Date Issued
2020
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Version
Final published version
Abstract
© 2020 American Association for the Advancement of Science. All rights reserved. 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.
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
Persistent DSpace Link
DOI of Published Version
10.1126/SCIADV.AAZ8521
