Derivation of a new model of lung adenocarcinoma using canine lung cancer organoids for translational research in pulmonary medicine

Yomogi Shiota Sato; Mohamed Elbadawy; Kazuhiko Suzuki; Ryouichi Tsunedomi; Hiroaki Nagano; Yusuke Ishihara; Haru Yamamoto; Daigo Azakami; Tsuyoshi Uchide; Ryuji Fukushima; Ryo Tanaka; Tomohiko Yoshida; Takuya Mori; Amira Abugomaa; Masahiro Kaneda; Hideyuki Yamawaki; Yuta Shinohara; Mohamed Aboubakr; Mohamed E El-Asrag; Tatsuya Usui; Kazuaki Sasaki

doi:10.1016/j.biopha.2023.115079

Derivation of a new model of lung adenocarcinoma using canine lung cancer organoids for translational research in pulmonary medicine

Biomed Pharmacother. 2023 Sep:165:115079. doi: 10.1016/j.biopha.2023.115079. Epub 2023 Jul 4.

Authors

Yomogi Shiota Sato¹, Mohamed Elbadawy², Kazuhiko Suzuki³, Ryouichi Tsunedomi⁴, Hiroaki Nagano⁴, Yusuke Ishihara¹, Haru Yamamoto¹, Daigo Azakami⁵, Tsuyoshi Uchide⁶, Ryuji Fukushima⁷, Ryo Tanaka⁸, Tomohiko Yoshida⁸, Takuya Mori⁹, Amira Abugomaa¹⁰, Masahiro Kaneda¹¹, Hideyuki Yamawaki¹², Yuta Shinohara¹³, Mohamed Aboubakr¹⁴, Mohamed E El-Asrag¹⁵, Tatsuya Usui¹⁶, Kazuaki Sasaki¹

Affiliations

¹ Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
² Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan; Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, 13736, Moshtohor, Toukh, Elqaliobiya, Egypt. Electronic address: Mohamed.elbadawy@fvtm.bu.edu.eg.
³ Laboratory of Veterinary Toxicology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
⁴ Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
⁵ Laboratory of Veterinary Clinical Oncology, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
⁶ Laboratory of Veterinary Molecular Pathology and Therapeutics, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
⁷ Animal Medical Emergency Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
⁸ Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
⁹ Kinki Animal Medical Study Center, 3-15-27, Hishie, Osaka 578-0984, Japan.
¹⁰ Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan; Faculty of Veterinary Medicine, Mansoura University, 35516 Mansoura, Egypt.
¹¹ Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
¹² Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, 35-1, Higashi 23 ban-cho, Towada, Aomori 034-8628, Japan.
¹³ Pet Health & Food Division, Iskara Industry CO., LTD, 1-14-2, Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan.
¹⁴ Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan; Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, 13736, Moshtohor, Toukh, Elqaliobiya, Egypt.
¹⁵ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
¹⁶ Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan. Electronic address: fu7085@go.tuat.ac.jp.

PMID: 37413906
DOI: 10.1016/j.biopha.2023.115079

Abstract

Canine primary lung cancer (cPLC) is a rare malignant tumor in dogs, and exhibits poor prognosis. Effective therapeutic drugs against cPLC have not been established yet. Also, cPLC resembles human lung cancer in histopathological characteristics and gene expression profiles and thus could be an important research model for this disease. Three-dimensional organoid culture is known to recapitulate the tissue dynamics in vivo. We, therefore, tried to generate cPLC organoids (cPLCO) for analyzing the profiles of cPLC. After samples from cPLC and the corresponding normal lung tissue were collected, cPLCO were successfully generated, which recapitulated the tissue architecture of cPLC, expressed lung adenocarcinoma marker (TTF1), and exhibited tumorigenesis in vivo. The sensitivity of cPLCO to anti-cancer drugs was different among strains. RNA-sequencing analysis showed significantly upregulated 11 genes in cPLCO compared with canine normal lung organoids (cNLO). Moreover, cPLCO were enriched with the MEK-signaling pathway compared with cNLO. The MEK inhibitor, trametinib decreased the viability of several strains of cPLCO and inhibited the growth of cPLC xenografts. Collectively, our established cPLCO model might be a useful tool for identifying novel biomarkers for cPLC and a new research model for dog and human lung cancer.

Keywords: C-MYC; Canine; Lung cancer; MEK inhibitor; Organoids; RNA seq.

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Adenocarcinoma of Lung* / genetics
Adenocarcinoma of Lung* / metabolism
Animals
Dogs
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Mitogen-Activated Protein Kinase Kinases / metabolism
Organoids
Pulmonary Medicine*
Translational Research, Biomedical

Substances

Mitogen-Activated Protein Kinase Kinases