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

Sau Yee Kok,Kazuhiro Murakami,Mizuho Nakayama,Kohei Miyazono,Masanobu Oshima,Hiroki R Ueda,Hiroko Oshima,Kei Takahashi

doi:10.1038/s41467-021-21160-0

Sau Yee Kok, Kazuhiro Murakami + Show 6 more

Open Access

https://doi.org/10.1038/s41467-021-21160-0

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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.

Highlights

A concept of polyclonal metastasis has recently been proposed, wherein tumor cell clusters break off from the primary site and are disseminated
At day 3 after spleen transplantation, tumor cell clusters including >10 cells were frequently found inside the sinusoid vessels of the liver, and the majority of tumor clusters consisted of a mixture of Venusand tdTomato-labeled cells (Fig. 1b, c)
We showed that non-metastatic intestinal tumor cells with a low accumulation of driver mutations can metastasize to the liver via a polyclonal mechanism

Summary

Introduction

A concept of polyclonal metastasis has recently been proposed, wherein tumor cell clusters break off from the primary site and are disseminated. Most studies that contributed to the polyclonal metastasis concept used differentially labeled but genetically identical or similar cancer cells, so how genetically heterogenous cells in the primary tumors are selected for cluster formation and colonization in the distant organs by the polyclonal mechanism remains unclear. To answer this question, we performed spleen transplantation experiments using a recently established organoid transplantation model[8,11]. We demonstrate that non-metastatic cells can metastasize when co-disseminated with metastatic cells through the generation of a fibrotic microenvironment in the arrested liver vessels

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