Nature Communications (Sep 2023)
THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer
- Mayuki Omatsu,
- Yuki Nakanishi,
- Kosuke Iwane,
- Naoki Aoyama,
- Angeles Duran,
- Yu Muta,
- Anxo Martinez-Ordoñez,
- Qixiu Han,
- Nobukazu Agatsuma,
- Kenta Mizukoshi,
- Munenori Kawai,
- Go Yamakawa,
- Mio Namikawa,
- Kensuke Hamada,
- Yuichi Fukunaga,
- Takahiro Utsumi,
- Makoto Sono,
- Tomonori Masuda,
- Akitaka Hata,
- Osamu Araki,
- Munemasa Nagao,
- Takaaki Yoshikawa,
- Satoshi Ogawa,
- Yukiko Hiramatsu,
- Motoyuki Tsuda,
- Takahisa Maruno,
- Toshiaki Kogame,
- Hiroaki Kasashima,
- Nobuyuki Kakiuchi,
- Masahiro M. Nakagawa,
- Kenji Kawada,
- Masakazu Yashiro,
- Kiyoshi Maeda,
- Yasuyuki Saito,
- Takashi Matozaki,
- Akihisa Fukuda,
- Kenji Kabashima,
- Kazutaka Obama,
- Seishi Ogawa,
- Nader Sheibani,
- Maria T. Diaz-Meco,
- Jorge Moscat,
- Hiroshi Seno
Affiliations
- Mayuki Omatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Kosuke Iwane
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Naoki Aoyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Angeles Duran
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
- Yu Muta
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
- Anxo Martinez-Ordoñez
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
- Qixiu Han
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
- Nobukazu Agatsuma
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Kenta Mizukoshi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Munenori Kawai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Go Yamakawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Mio Namikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Kensuke Hamada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Yuichi Fukunaga
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Takahiro Utsumi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Makoto Sono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Tomonori Masuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Akitaka Hata
- Department of Dermatology, Kyoto University Graduate School of Medicine
- Osamu Araki
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Munemasa Nagao
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Takaaki Yoshikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Satoshi Ogawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Yukiko Hiramatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Toshiaki Kogame
- Department of Dermatology, Kyoto University Graduate School of Medicine
- Hiroaki Kasashima
- Department of Gastroenterological Surgery, Osaka Metropolitan University
- Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Masahiro M. Nakagawa
- Department of Pathology and Tumor Biology, Kyoto University
- Kenji Kawada
- Department of Gastrointestinal Surgery, Kyoto University, Graduate School of Medicine
- Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka Metropolitan University
- Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University
- Yasuyuki Saito
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine
- Takashi Matozaki
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine
- Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine
- Kazutaka Obama
- Department of Gastrointestinal Surgery, Kyoto University, Graduate School of Medicine
- Seishi Ogawa
- Department of Pathology and Tumor Biology, Kyoto University
- Nader Sheibani
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-
- Maria T. Diaz-Meco
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
- Jorge Moscat
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
- Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine
- DOI
- https://doi.org/10.1038/s41467-023-41095-y
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 19
Abstract
Abstract Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.
