A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour-immune cell communication.
A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour-immune cell communication.
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前列腺癌肝转移的新型小鼠模型揭示了动态肿瘤免疫细胞通讯。
DOI：
10.1111/cpr.13056
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发表时间：
2021-07
影响因子：
8.5
通讯作者：
Zhang K
中科院分区：
文献类型：
--
作者：
Liu K;Jing N;Wang D;Xu P;Wang J;Chen X;Cheng C;Xin Z;He Y;Zhao H;Ji Z;Zhang P;Gao WQ;Zhu HH;Zhang K
与晚期前列腺癌（PCa）骨转移的广泛研究相比，迄今为止对肝转移的研究不足。为了解释晚期PCa肝转移的分子和细胞机制，我们通过原位注射PbCre+; rb 1f/f; p53 f/f小鼠的类器官，开发了一种快速且免疫充分的PCa肝转移小鼠模型。PbCre+; rb 1f/f; p53 f/f和PbCre+;ptenf/f; p53 f/f小鼠用于体外产生PCa类器官培养物。通过将类器官原位移植到C57 BL/6小鼠的前列腺中来建立免疫充分的肝转移模型。进行免疫荧光和免疫组织化学染色，以表征原发性肿瘤和类器官源性肿瘤（ODT）的谱系特征。可以通过生物发光成像系统可视化感染ODT的小生境标记报告基因的生长。通过流式细胞术测定与肝转移灶中的肿瘤细胞通讯的免疫细胞。在免疫完整的小鼠中建立具有完全转移的PCa肝转移模型。该模型重建了原始肿瘤的组织学和谱系特征，并揭示了肝转移灶中动态的肿瘤免疫细胞通讯。我们的研究结果表明，缺乏CD 8 + T细胞和CD 163 + M2样巨噬细胞以及PD 1 + CD 4 + T细胞的富集有助于PCa肝转移的免疫抑制微环境。我们的模型可以作为一个可靠的工具，用于分析的分子发病机制和肿瘤免疫细胞串扰在肝转移的PCa，并可能被用作一个有价值的体内模型的治疗开发。Liu等人通过原位注射PbCre+; rb 1f/f; p53 f/f小鼠的类器官培养物，开发了一种快速且免疫充分的前列腺癌肝转移小鼠模型。使用小生境标记的慢病毒报告基因，描绘了肝转移小生境中不同阶段的动态肿瘤免疫细胞通讯。缺乏CD 8 + T细胞和丰富的PD 1 + CD 4 + T细胞和CD 163 + M2巨噬细胞有助于免疫抑制性肝转移小生境。
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+; rb1f/f;p53f/f mice. PbCre+;rb1f/f;p53f/f and PbCre+;ptenf/f;p53f/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. 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. 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. Liu et al. developed a rapid and immune sufficient mouse model for liver metastasis of prostate cancer via orthotopic injection of organoid cultures from PbCre+; rb1f/f;p53f/f mice. Using a niche‐labeling lentiviral reporter, a dynamic tumor‐immune cell communication at different phases in the liver metastatic niche is depicted. A paucity of CD8+ T cells and abundant PD1+ CD4+ T cells and CD163+ M2 macrophages contribute to an immune suppressive liver metastatic niche.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
64.8
作者：
Ombrato, Luigi;Nolan, Emma;Malanchi, Ilaria
通讯作者：
Malanchi, Ilaria
影响因子：
23.4
作者：
Humid, Anis A.;Gray, Kathryn P.;Sweeney, Christopher J.
通讯作者：
Sweeney, Christopher J.
影响因子：
13.5
作者：
Ma, Bo;Wheeler, Sarah E.;Clark, Amanda M.;Whaley, Diana L.;Yang, Min;Wells, Alan
通讯作者：
Wells, Alan
影响因子：
11.2
作者：
Zhou, Zongxiang;Flesken-Nikitin, Andrea;Nikitin, Alexander Yu.
通讯作者：
Nikitin, Alexander Yu.