2. Academic Validation
  3. ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer

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

  • Mol Cancer. 2025 Apr 16;24(1):116. doi: 10.1186/s12943-025-02312-y.
Hibiki Umeda # 1,  Kunitoshi Shigeyasu 2,  Toshiaki Takahashi # 1,  Kazuya Moriwake # 1,  Yoshitaka Kondo 1,  Kazuhiro Yoshida 1,  Sho Takeda 1,  Shuya Yano 1 3,  Yuki Matsumi 1,  Hiroyuki Kishimoto 1,  Tomokazu Fuji 4,  Kazuya Yasui 1,  Hideki Yamamoto 5,  Kosei Takagi 1,  Masashi Kayano 1,  Hiroyuki Michiue 6,  Keiichiro Nakamura 7,  Yoshiko Mori 1 8,  Fuminori Teraishi 1,  Hiroshi Tazawa 1,  Yuzo Umeda 1 9,  Shunsuke Kagawa 1,  Ajay Goel 10,  Toshiyoshi Fujiwara 1
Affiliations

Affiliations

  • 1 Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • 2 Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. gmd421045@s.okayama-u.ac.jp.
  • 3 Department of Digestive Surgery, Kawasaki Medical School, Okayama, Japan.
  • 4 Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. pri958hs@s.okayama-u.ac.jp.
  • 5 Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • 6 Neutron Therapy Research Center, Okayama University, Okayama, Japan.
  • 7 Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • 8 Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
  • 9 Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.
  • 10 Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
  • # Contributed equally.
PMID: 40241135 DOI: 10.1186/s12943-025-02312-y
Abstract

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.

Keywords

Biomarker; Chemoresistance; Colorectal cancer; Macrophage; RNA-editing.

Figures
Products