Journal Article

ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer

Takeda, Sho, Matsumi, Yuki, Kayano, Masashi, Takagi, Kosei, Fuji, Tomokazu, Kagawa, Shunsuke, Umeda, Yuzo, Yoshida, Kazuhiro, Fujiwara, Toshiyoshi, Yasui, Kazuya, Umeda, Hibiki, Yamamoto, Hideki, Takahashi, Toshiaki, Moriwake, Kazuya, Michiue, Hiroyuki, Kondo, Yoshitaka, Nakamura, Keiichiro, Tazawa, Hiroshi, Teraishi, Fuminori, Yano, Shuya, Kishimoto, Hiroyuki, Mori, Yoshiko, Shigeyasu, Kunitoshi, Goel, Ajay

2025

Overview

Background Colorectal cancer (CRC) is considered the third most common type of cancer worldwide. Tumor-associated macrophages (TAMs) have been shown to promote drug resistance. Adenosine-to-inosine RNA-editing, as regulated by adenosine deaminase acting on RNA (ADAR), is a process that induces the posttranscriptional modification of critical oncogenes. The aim of this study is to determine whether the signals from cancer cells would induce RNA-editing in macrophages. Methods The effects of RNA-editing on phenotypes in macrophages were analyzed using clinical samples and in vitro and in vivo models. Results The intensity of the RNA-editing enzyme ADAR1 (Adenosine deaminase acting on RNA 1) in cancer and mononuclear cells indicated a strong positive correlation between the nucleus and cytoplasm. The ADAR1-positive mononuclear cells were positive for CD68 and CD163, a marker for M2 macrophages. Cancer cells transport pro-inflammatory cytokines or ADAR1 protein directly to macrophages via the exosomes, promoting RNA-editing in AZIN1 (Antizyme Inhibitor 1) and GLI1 (Glioma-Associated Oncogene Homolog 1) and resulting in M2 macrophage polarization. GLI1 RNA-editing in the macrophages induced by cancer cells promotes the secretion of SPP1, which is supplied to the cancer cells. This activates the NFκB pathway in cancer cells, promoting oxaliplatin resistance. When the JAK inhibitors were administered, oncogenic RNA-editing in the macrophages was suppressed. This altered the macrophage polarization from M2 to M1 and decreased oxaliplatin resistance in cancer cells. Conclusions This study revealed that ADAR1-high TAMs are crucial in regulating drug resistance in CRC and that targeting ADAR1 in TAMs could be a promising treatment approach for overcoming drug resistance in CRC.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenosine / Adenosine deaminase / Adenosine Deaminase - genetics / Adenosine Deaminase - metabolism / Animals / Biomarker / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer therapies / CD163 antigen / Cell Line, Tumor / Chemoresistance / Chemotherapy / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / Cytoplasm / Drug resistance / Drug Resistance, Neoplasm - genetics / Drug therapy / Editing / Enzymes / Exosomes / Fibroblasts / Gene Expression Regulation, Neoplastic / Health aspects / Humans / Kinases / Leukocytes (mononuclear) / Lymphatic system / Macrophage / Macrophages / Medical prognosis / Metastasis / Mice / NF-κB protein / Oncogenes / Oncology / Oxaliplatin / Phenotypes / Polarization / Post-transcription / Ribonucleic acid / RNA / RNA Editing / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Therapeutic targets / Tumor-Associated Macrophages - metabolism / Tumors / Xenograft Model Antitumor Assays