Biology subjects

Azuma, K.

Publications and source records attributed to Azuma, K..

3 recordsLinked to original sources

bioRxiv2025

Spatial dynamics of the tumor microenvironment in emerging resistance to targeted therapy in EGFR-mutated NSCLC

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide therapeutic benefit in EGFR mutation-positive non-small cell lung cancer, but some individuals develop early resistance. We performed spatial transcriptomics analysis of pre- and posttreatment tumor samples from the same patients to explore the underlying mechanisms of such early resistance. The proportion and activation of fibroblasts increased in association with the development of early resistance, whereas a distinct tumor cell cluster showed activation of tumor necrosis factor- signaling via the NF-{kappa}B pathway even before treatment. Also in the early resistance sample, specific tumor cell clusters interacted with immune and stromal cells. Immature tertiary lymphoid structures (TLSs) were enriched in the early resistance sample, whereas mature TLSs were observed in the long-term response sample. These findings implicate tumor heterogeneity and an inflammatory tumor microenvironment in early EGFR-TKI resistance, providing insight into potential therapeutic strategies to improve treatment outcomes.

cancer biology↗

bioRxiv2021

Metastatic profiling of HER2-positive breast cancer cell lines in xenograft models

Most studies on breast cancer metastasis have been performed using triple-negative breast cancer (TNBC) cells; thus, subtype-dependent metastatic ability of breast cancer is poorly understood. In this research, we performed intravenous injection (IVI) and intra-caudal arterial injections (CAI) using nine human epidermal growth factor receptor-2 (HER2)-positive breast cancer cell lines for evaluating their metastatic abilities. Our results showed that MDA-MB-453, UACC-893, and HCC-202 had strong bone metastatic abilities, whereas HCC-2218 and HCC-1419 did not show bone metastasis. HER2-positive cell lines could hardly metastasize to the lung through IVI. From the genomic analysis, gene signatures were extracted according to the breast cancer subtypes and their metastatic preferences. The UACC-893 cell line was identified as a useful model for the metastasis study of HER2-positive breast cancer. Combined with our previous result on brain proliferation ability, we provide a characteristic metastasis profile of HER2-positive breast cancer cell lines in this study. Statements and DeclarationsO_ST_ABSFundingC_ST_ABSThis study was supported by JSPS KAKENHI (grant no. 18K16269: Grant-in-Aid for Early-Career Scientist to J.N.; grant no. 20J01794, Grant-in-Aid for JSPS fellows to J.N.; grant no. 20J23297, Grant-in-Aid for JSPS fellows to Y.H.) and partially supported by the grants for translational research programs from Fukushima Prefecture (S.W. and K.S.). AuthorshipYH and KA performed the in vivo experiments and bioinformatical analyses. SW, and KS interpreted the data. YH, KA, and JN wrote the manuscript. JN conceived and designed the study. All the authors reviewed and edited the manuscript. Competing InterestsThe authors declare that they have no competing interests. Ethical approvalThe animal experiments were conducted under the approval of the ethics committee of Waseda University (2020-A067, 2021-A074).

cancer biology↗

bioRxiv2019

RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization

Inflammation plays an important role in pathologic angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation, however its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1K45A/K45A mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization (CNV), Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis was mediated by caspase activation through a kinase-independent function of RIP1 and RIP3, and simultaneous caspase inhibition with RIP1 kinase inhibition abrogated the effects of RIP1 kinase inhibition on angiogenesis in vivo. Mechanistically, infiltrating macrophages are the key target for RIP1 kinase inhibition to attenuate pathological angiogenesis, and we observed that the inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of pro-angiogenic M2-like markers while M1 marker expressions were sustained. Similarly, in vitro, catalytic inhibition of RIP1 down-regulated M2 marker expressions in IL-4-activated bone marrow-derived macrophages, which was blocked by simultaneous caspase inhibition. Taken together, these results suggest a novel, non-necrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may represent a therapeutic target for the control of angiogenesis-related diseases.\n\nSignificancePathological angiogenesis has been implicated in diverse pathologies. Infiltrating macrophages, especially those activated to M2-like phenotype are critically important to support angiogenesis. Whereas the role of RIP1 kinase in the regulation of apoptosis, necroptosis, and inflammation have been well established, its role in angiogenesis remains elusive despite being abundantly expressed in angiogenesis-related infiltrating macrophages. This study demonstrated for the first time that RIP1 kinase inhibition attenuates angiogenesis in multiple mouse models of pathological angiogenesis in vivo. Mechanistically, the inhibitory effect on angiogenesis depends on RIP kinase inhibition-mediated caspase activation in infiltrating macrophages that suppresses M2-like polarization, thereby attenuating pathological angiogenesis.

molecular biology↗