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.