Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer

Nat Commun. 2021 Apr 16;12(1):2281. doi: 10.1038/s41467-021-22450-3.

Takashi Nishina ¹, Yutaka Deguchi ², Daisuke Ohshima ³, Wakami Takeda ² ⁴, Masato Ohtsuka ⁵ ⁶, Shigeyuki Shichino ⁷, Satoshi Ueha ⁷, Soh Yamazaki ², Mika Kawauchi ², Eri Nakamura ⁸, Chiharu Nishiyama ⁴, Yuko Kojima ⁹, Satomi Adachi-Akahane ³, Mizuho Hasegawa ¹⁰, Mizuho Nakayama ¹¹, Masanobu Oshima ¹¹, Hideo Yagita ¹², Kazutoshi Shibuya ¹³, Tetuo Mikami ¹⁴, Naohiro Inohara ¹⁰, Kouji Matsushima ⁷, Norihiro Tada ⁸, Hiroyasu Nakano ¹⁵ ¹⁶

Affiliations

1 Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan. [email protected].
2 Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
3 Department of Physiology, Toho University School of Medicine, Tokyo, Japan.
4 Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan.
5 Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, Isehara, Kanagawa, Japan.
6 The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan.
7 Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.
8 Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan.
9 Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
10 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
11 WPI Nano Life Science Institute (WPI-Nano LSI), Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
12 Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
13 Department of Surgical Pathology, Toho University School of Medicine, Tokyo, Japan.
14 Department of Pathology, Toho University School of Medicine, Tokyo, Japan.
15 Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan. [email protected].
16 Host Defense Research Center, Toho University School of Medicine, Tokyo, Japan. [email protected].

PMID: 33863879 DOI: 10.1038/s41467-021-22450-3

Abstract

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11⁺) cells are not fully understood. To characterize IL-11⁺ cells in vivo, we generate Il11 reporter mice. IL-11⁺ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal Cancer. IL-11⁺ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human Cancer database analysis reveals that the expression of genes enriched in IL-11⁺ fibroblasts is elevated in human colorectal Cancer and correlated with reduced recurrence-free survival. IL-11⁺ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.

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