Dataset Information

A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour-immune cell communication.

ABSTRACT:

Objectives

In contrast to extensive studies on bone metastasis in advanced prostate cancer (PCa), liver metastasis has been under-researched so far. In order to decipher molecular and cellular mechanisms underpinning liver metastasis of advanced PCa, we develop a rapid and immune sufficient mouse model for liver metastasis of PCa via orthotopic injection of organoids from PbCre⁺ ; rb1^f/f ;p53^f/f mice.

Materials and methods

PbCre⁺ ;rb1^f/f ;p53^f/f and PbCre⁺ ;pten^f/f ;p53^f/f mice were used to generate PCa organoid cultures in vitro. Immune sufficient liver metastasis models were established via orthotopic transplantation of organoids into the prostate of C57BL/6 mice. Immunofluorescent and immunohistochemical staining were performed to characterize the lineage profile in primary tumour and organoid-derived tumour (ODT). The growth of niche-labelling reporter infected ODT can be visualized by bioluminescent imaging system. Immune cells that communicated with tumour cells in the liver metastatic niche were determined by flow cytometry.

Results

A PCa liver metastasis model with full penetrance is established in immune-intact mouse. This model reconstitutes the histological and lineage features of original tumours and reveals dynamic tumour-immune cell communication in liver metastatic foci. Our results suggest that a lack of CD8⁺ T cell and an enrichment of CD163⁺ M2-like macrophage as well as PD1⁺ CD4⁺ T cell contribute to an immuno-suppressive microenvironment of PCa liver metastasis.

Conclusions

Our model can be served as a reliable tool for analysis of the molecular pathogenesis and tumour-immune cell crosstalk in liver metastasis of PCa, and might be used as a valuable in vivo model for therapy development.

SUBMITTER: Liu K

PROVIDER: S-EPMC8249794 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour-immune cell communication.

Liu Kaiyuan K Jing Na N Wang Deng D Xu Penghui P Wang Jinming J Chen Xinyu X Cheng Chaping C Xin Zhixiang Z He Yuman Y Zhao Huifang H Ji ZhongZhong Z Zhang Pengcheng P Gao Wei-Qiang WQ Zhu Helen He HH Zhang Kai K

Cell proliferation 20210521 7

<h4>Objectives</h4>In contrast to extensive studies on bone metastasis in advanced prostate cancer (PCa), liver metastasis has been under-researched so far. In order to decipher molecular and cellular mechanisms underpinning liver metastasis of advanced PCa, we develop a rapid and immune sufficient mouse model for liver metastasis of PCa via orthotopic injection of organoids from PbCre<sup>+</sup> ; rb1<sup>f/f</sup> ;p53<sup>f/f</sup> mice.<h4>Materials and methods</h4>PbCre<sup>+</sup> ;rb1<su ...[more]

PMID: 34021647

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Project description: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, Stellarhigh PGC-like tumor cells, but not Stellarlow 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.

Dataset Information

A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour-immune cell communication.

Objectives

Materials and methods

Results

Conclusions

Publications

A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour-immune cell communication.

Similar Datasets

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