The periosteum provides a stromal defence against cancer invasion into the bone

Kazutaka Nakamura, Masayuki Tsukasaki (), Takaaki Tsunematsu, Minglu Yan, Yutaro Ando, Nam Cong-Nhat Huynh, Kyoko Hashimoto, Qiao Gou, Ryunosuke Muro, Ayumi Itabashi, Takahiro Iguchi, Kazuo Okamoto, Takashi Nakamura, Kenta Nakano, Tadashi Okamura, Tomoya Ueno, Kosei Ito, Naozumi Ishimaru, Kazuto Hoshi and Hiroshi Takayanagi ()
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Kazutaka Nakamura: The University of Tokyo
Masayuki Tsukasaki: The University of Tokyo
Takaaki Tsunematsu: Tokushima University Graduate School of Biomedical Sciences
Minglu Yan: The University of Tokyo
Yutaro Ando: The University of Tokyo
Nam Cong-Nhat Huynh: University of Medicine and Pharmacy at Ho Chi Minh City
Kyoko Hashimoto: The University of Tokyo
Qiao Gou: The University of Tokyo
Ryunosuke Muro: The University of Tokyo
Ayumi Itabashi: The University of Tokyo
Takahiro Iguchi: The University of Tokyo
Kazuo Okamoto: The University of Tokyo
Takashi Nakamura: Tokyo Dental College
Kenta Nakano: National Center for Global Health and Medicine
Tadashi Okamura: National Center for Global Health and Medicine
Tomoya Ueno: Nagasaki University
Kosei Ito: Nagasaki University
Naozumi Ishimaru: Tokyo Medical and Dental University
Kazuto Hoshi: The University of Tokyo
Hiroshi Takayanagi: The University of Tokyo

Nature, 2024, vol. 634, issue 8033, 474-481

Abstract: Abstract The periosteum is the layer of cells that covers nearly the entire surface of every bone. Upon infection, injury or malignancy the bone surface undergoes new growth—the periosteal reaction—but the mechanism and physiological role of this process remain unknown1,2. Here we show that the periosteal reaction protects against cancer invasion into the bone. Histological analyses of human lesions of head and neck squamous cell carcinomas (HNSCCs) show that periosteal thickening occurs in proximity to the tumour. We developed a genetically dissectible mouse model of HNSCC and demonstrate that inducible depletion of periosteal cells accelerates cancerous invasion of the bone. Single-cell RNA sequencing reveals that expression of the gene encoding the protease inhibitor TIMP1 is markedly increased in the periosteum at the pre-invasive stage. This increase is due to upregulation of HIF1α expression in the tumour microenvironment, and increased TIMP1 inactivates matrix-degrading proteases, promoting periosteal thickening to inhibit cancer invasion. Genetic deletion of Timp1 impairs periosteal expansion, exacerbating bone invasion and decreasing survival in tumour-bearing mice. Together, these data show that the periosteal reaction may act as a functional stromal barrier against tumour progression, representing a unique example of tissue immunity mediated by stromal cells.

Date: 2024
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DOI: 10.1038/s41586-024-07822-1

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