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

• Published in: Nature communications 2021-02, Vol.12 (1), p.863-14, Article 863
• Main Authors: Kok, Sau Yee, Oshima, Hiroko, Takahashi, Kei, Nakayama, Mizuho, Murakami, Kazuhiro, Ueda, Hiroki R., Miyazono, Kohei, Oshima, Masanobu
• Format: Article
• Language: English
• Subjects: 13/106; 13/51; 14/35; 14/63; 59/5; 631/67/1504/1885; 631/67/2329; 631/67/70; 64/60; Animals; Cell activation; Cell Aggregation; Cell Proliferation; Cell survival; Clone Cells; Clusters; Colonization; Depletion; Fibrosis; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatocytes; Humanities and Social Sciences; Liver; Liver - blood supply; Liver - pathology; Metastases; Metastasis; Mice; Mice, Inbred NOD; Microenvironments; multidisciplinary; Mutation; Neoplasm Metastasis - pathology; Neoplasms - genetics; Neoplasms - pathology; Organoids - pathology; Phenotype; Science; Science (multidisciplinary); Sine waves; Spleen; Spleen - transplantation; Transforming Growth Factor beta - pharmacology; Transplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21160-0

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. Cancer cell clusters metastasize to distant organ by polyclonal manner. Here, the authors show that malignant subclone induces fibrotic niche generation in the liver by hepatic stellate cell activation, supporting survival and colonization of non-metastatic cells to develop polyclonal metastasis.