Nao Nishida-Aoki

1. Myocardial fibrosis is a common pathological feature of various cardiovascular diseases and is recognized as a marker of poor prognosis. Following myocardial infarction (MI), replacement fibrosi...

Tumor tissue is densely packed with cancer cells, non‐cancerous cells, and ECM, forming functional structures. Cancer cells transfer extracellular vesicles (EVs) to modify surrounding normal cells into cancer‐promoting cells, establishing a tumor‐favorable environment together with other signaling molecules and structural components. Such tissue environments largely affect cancer cell properties, and so as EV‐mediated cellular communications within tumor tissue. However, current research on EVs focuses on functional analysis of vesicles isolated from the liquid phase, including cell culture supernatants and blood draws, 2D‐cultured cell assays, or systemic analyses on animal models for biodistribution. Therefore, we have a limited understanding of local EV transfer within tumor tissues. In this review, we discuss the need to study EVs in a physiological tissue context by summarizing the current findings on the impacts of tumor tissue environment on cancer EV properties and transfer and the techniques required for the analysis. Tumor tissue environment is likely to alter EV properties, pose physical barriers, interactions, and interstitial flows for the dynamics, and introduce varieties in the cell types taken up. Utilizing physiological experimental settings and spatial analyses, we need to tackle the remaining questions on physiological EV‐mediated cancer–host cell interactions. Understanding cancer EV‐mediated cellular communications in physiological tumor tissues will lead to developing interaction‐targeting therapies and provide insight into EV‐mediated non‐cancerous cells and interspecies interactions.

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 TAMs in 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.