Polypharmacologic Reprogramming of Tumor-Associated Macrophages toward an Inflammatory Phenotype

Nao Nishida-Aoki, Taranjit S. Gujral*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Tumor-associated macrophages (TAM) are an important component of the tumor microenvironment (TME) that can promote tumor progression, metastasis, and resistance to therapies. Although TAMs represent a promising target for therapeutic intervention, the complexity of the TME has made the study of TAMs challenging. Here, we established a physiologically relevant in vitro TAM polarization system that recapitulates TAM protumoral activities. This system was used to characterize dynamic changes in gene expression and protein phosphorylation during TAM polarization and to screen phenotypic kinase inhibitors that impact TAM programming. BMS-794833, a multitargeted compound, was identified as a potent inhibitor of TAM polarization. BMS-794833 decreased protumoral properties of TAMsin vitro and suppressed tumor growth in mouse triple-negative breast cancer models. The effect of BMS-794833 was independent of its primary targets (MET and VEGFR2) but was dependent on its effect on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAPKs. Collectively, these findings underline the efficacy of polypharmacologic strategies in reprogramming complex signaling cascades activated during TAM polarization. Significance: A physiologically relevant in vitro system of TAM polarization uncovers signaling pathways that regulate polarization and identifies strategies to target macrophage reprogramming to suppress cancer growth.

Original languageEnglish
Pages (from-to)433-446
Number of pages14
JournalCancer Research
Volume82
Issue number3
DOIs
Publication statusPublished - 2022 Feb 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Polypharmacologic Reprogramming of Tumor-Associated Macrophages toward an Inflammatory Phenotype'. Together they form a unique fingerprint.

Cite this