A novel tdTomato transgenic mouse model to visualize FAP-positive cancer-associated fibroblasts

Feng Wei; Tomoyuki Uchihara; Atsuko Yonemura; Noriko Yasuda-Yoshihara; Tadahito Yasuda; Takashi Semba; Masahiro Fukuda; Takahiko Akiyama; Fumimasa Kitamura; Luke Bu; Xichen Hu; Lingfeng Fu; Jun Zhang; Ryusho Kariya; Juntaro Yamasaki; Kazuki Aihara; Kohei Yamashita; Osamu Nagano; Seiji Okada; Hideo Baba; Takatsugu Ishimoto

doi:10.1111/febs.16712

A novel tdTomato transgenic mouse model to visualize FAP-positive cancer-associated fibroblasts

FEBS J. 2023 May;290(10):2604-2615. doi: 10.1111/febs.16712. Epub 2023 Jan 3.

Authors

Feng Wei^{1

2}, Tomoyuki Uchihara^{1

2}, Atsuko Yonemura^{1

2}, Noriko Yasuda-Yoshihara^{1

2}, Tadahito Yasuda^{1

2}, Takashi Semba^{1

2}, Masahiro Fukuda^{2

3}, Takahiko Akiyama^{1

2}, Fumimasa Kitamura^{1

2}, Luke Bu^{1

2}, Xichen Hu^{1

2}, Lingfeng Fu^{1

2}, Jun Zhang^{1

2}, Ryusho Kariya⁴, Juntaro Yamasaki⁵, Kazuki Aihara^{2

6}, Kohei Yamashita¹, Osamu Nagano⁵, Seiji Okada⁴, Hideo Baba^{1

7}, Takatsugu Ishimoto^{1

2}

Affiliations

¹ Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
² Gastrointestinal Cancer Biology, International Research Center of Medical Sciences (IRCMS), Kumamoto University, Japan.
³ Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore City, Singapore.
⁴ Division of Haematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Japan.
⁵ Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
⁶ Department of Surgery, National Defense Medical College, Saitama, Japan.
⁷ Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Japan.

PMID: 36565059
DOI: 10.1111/febs.16712

Abstract

Fibroblast activation protein (FAP) generally shows low or undetectable expression in most normal tissues but is highly expressed in fibroblasts in almost all carcinomas. FAP is one of the potential molecules to detect activated fibroblasts and has multiple roles in tumour progression. We generated transgenic mice that specifically expressed tdTomato along with FAP promoter activity. Coculturing a mouse gastric cancer cell line and FAP-tdTomato transgenic mouse-derived fibroblasts showed that tdTomato expression was elevated in the cocultured fibroblasts. Moreover, stomach wall transplanted tumours in mice also showed FAP-tdTomato expression in fibroblasts of the stomach and each metastatic legion. These results indicated that FAP-tdTomato expression in fibroblasts was elevated by stimulation through the interaction with cancer cells. Functionally, collagen production was increased in FAP/tdTomato-positive fibroblasts cocultured with mouse cancer cells. These FAP-tdTomato transgenic mice have the potential to be used to investigate real-time FAP dynamics and the importance of FAP expression in tumour development.

Keywords: cancer-associated fibroblasts; fibroblast activation protein; transgenic mouse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cancer-Associated Fibroblasts* / metabolism
Endopeptidases / genetics
Endopeptidases / metabolism
Fibroblasts / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Transgenic
Red Fluorescent Protein
Serine Endopeptidases / genetics
Serine Endopeptidases / metabolism
Stomach Neoplasms* / pathology

Substances

Serine Endopeptidases
Endopeptidases
Membrane Proteins