Identification of primordial germ cell-like cells as liver metastasis initiating cells in mouse tumour models

Chunfang Liu; Zhan Ma; Zhen Cai; Fengyu Zhang; Cheng Liu; Tingjin Chen; Danni Peng; Xiaohong Xu; Hui-Kuan Lin

doi:10.1038/s41421-020-0145-3

Identification of primordial germ cell-like cells as liver metastasis initiating cells in mouse tumour models

Cell Discov. 2020 Mar 24:6:15. doi: 10.1038/s41421-020-0145-3. eCollection 2020.

Authors

Chunfang Liu^#^{1

2}, Zhan Ma^#¹, Zhen Cai², Fengyu Zhang¹, Cheng Liu¹, Tingjin Chen², Danni Peng², Xiaohong Xu³, Hui-Kuan Lin²

Affiliations

¹ 1Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040 China.
² 2Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA.
³ 3Department of breast surgery, First Affiliated Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, 310006 China.

^# Contributed equally.

Abstract

Liver metastasis, characterized by the spread of tumors to the liver from other areas, represents a deadly disease with poor prognosis. Currently, there is no effective therapeutic strategies and/or agents to combat liver metastasis primarily due to the insufficient understanding of liver metastasis. To develop a promising strategy for targeting liver metastasis, understanding of a cell origin responsible for liver metastasis and how this cell can be pharmacologically eliminated are therefore crucial. Using diverse tumor models including p53 ^-/- genetic mouse model and syngeneic tumor models, we identified primordial germ cell (PGC)-like tumor cells, which are enriched in earliest liver micro-metastasis (up to 99%), as a cell origin of liver metastasis. PGC-like tumor cells formed earliest micro-metastasis in liver and gradually differentiated into non-PGC-like tumor cells to constitute late macro-metastasis in the course of tumor metastasis. The liver metastasis-initiating cells (PGC-like tumor cells) display cell renewal and differentiation capabilities, resemble primordial germ cells (PGCs) in morphology and PGC marker gene expression, and express higher level of the genes linked to metastasis and immune escape compared with non-PGC-like tumor cells. Of note, Stellar^high PGC-like tumor cells, but not Stellar^low non-PGC-like cells, sorted from primary tumors of p53 ^-/- mice readily form liver metastasis. Depletion of PGC-like tumor cells through genetic depletion of any of key germ cell genes impairs liver metastasis, while increased PGC-like tumor cells by SMAD2 knockout is correlated with markedly enhanced liver metastasis. Finally, we present the proof of principle evidence that pharmacologically targeting BMP pathways serves as a promising strategy to eliminate PGC-like tumor cells leading to abrogating liver metastasis. Collectively, our study identifies PGC-like tumor cells as a cell origin of liver metastasis, whose depletion by genetically targeting core PGC developmental genes or pharmacologically inhibiting BMP pathways serves a promising strategy for targeting liver metastasis.

Keywords: Cancer; Mechanisms of disease.

Abstract

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