Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation

Sau Yee Kok, Hiroko Oshima, Kei Takahashi, Mizuho Nakayama, Kazuhiro Murakami, Hiroki R. Ueda, Kohei Miyazono and Masanobu Oshima ()
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Sau Yee Kok: Cancer Research Institute, Kanazawa University
Hiroko Oshima: Cancer Research Institute, Kanazawa University
Kei Takahashi: The University of Tokyo
Mizuho Nakayama: Cancer Research Institute, Kanazawa University
Kazuhiro Murakami: Cancer Research Institute, Kanazawa University
Hiroki R. Ueda: The University of Tokyo
Kohei Miyazono: The University of Tokyo
Masanobu Oshima: Cancer Research Institute, Kanazawa University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract A concept of polyclonal metastasis has recently been proposed, wherein tumor cell clusters break off from the primary site and are disseminated. However, the involvement of driver mutations in such polyclonal mechanism is not fully understood. Here, we show that non-metastatic AP cells metastasize to the liver with metastatic AKTP cells after co-transplantation to the spleen. Furthermore, AKTP cell depletion after the development of metastases results in the continuous proliferation of the remaining AP cells, indicating a role of AKTP cells in the early step of polyclonal metastasis. Importantly, AKTP cells, but not AP cells, induce fibrotic niche generation when arrested in the sinusoid, and such fibrotic microenvironment promotes the colonization of AP cells. These results indicate that non-metastatic cells can metastasize via the polyclonal metastasis mechanism using the fibrotic niche induced by malignant cells. Thus, targeting the fibrotic niche is an effective strategy for halting polyclonal metastasis.

Date: 2021
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DOI: 10.1038/s41467-021-21160-0

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