ScRNA-seq revealed an immunosuppression state and tumor microenvironment heterogeneity related to lymph node metastasis in prostate cancer

Experimental Hematology & Oncology

Research

Haojie Wang¹  Lijin Feng²  Qiong Cao³  Ziyao Li⁴  Weiyi Li⁴  Lin Ye⁴  Chaozhi Tang⁴  Xianchao Sun⁴  Wangli Mei⁴  Liang Jin⁴  Xiang Liu⁵  Shiyong Xin⁶  Jianguo Zhang⁷  Xinwei Feng⁸  Zhenhua Zhang⁹  Rong Wang^1,10 

[1] Department of Central Laboratory, Zhengzhou University, Luoyang Central Hospital, 471003, Luoyang, China;Department of Pathology, Jing’an District Zhabei Central Hospital, No.619, Zhonghuaxin Road, 200070, Shanghai, China;Department of Pathology, The Third Affiliated Hospital of Henan University of Science and Technology, 471003, Henan, China;Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, 200120, Shanghai, China;Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, 200120, Shanghai, China;Department of Urology, Putuo People’s Hospital, School of Medicine, Shanghai, China;Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, 200120, Shanghai, China;Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, 471003, Luoyang, China;Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, 471003, Luoyang, China;School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, 518107, Shenzhen, China;School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, China;School of Pharmacy, Inner Mongolia Medical University, 010000, Hohhot, China;

关键词: Prostate Cancer;    Metastasis;    Single-cell RNA sequencing;    Tumor Microenvironment;    Immunosuppression;   

DOI  :  10.1186/s40164-023-00407-0

 received in 2022-12-02, accepted in 2023-04-25,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMetastasis is a crucial aspect of disease progression leading to death in patients with prostate cancer (PCa). However, its mechanism remains unclear. We aimed to explore the mechanism of lymph node metastasis (LNM) by analyzing the heterogeneity of tumor microenvironment (TME) in PCa using scRNA-seq.MethodsA total of 32,766 cells were obtained from four PCa tissue samples for scRNA-seq, annotated, and grouped. InferCNV, GSVA, DEG functional enrichment analysis, trajectory analysis, intercellular network evaluation, and transcription factor analysis were carried out for each cell subgroup. Furthermore, validation experiments targeting luminal cell subgroups and CXCR4 + fibroblast subgroup were performed.ResultsThe results showed that only EEF2 + and FOLH1 + luminal subgroups were present in LNM, and they appeared at the initial stage of luminal cell differentiation, which were comfirmed by verification experiments. The MYC pathway was enriched in the EEF2 + and FOLH1 + luminal subgroups, and MYC was associated with PCa LNM. Moreover, MYC did not only promote the progression of PCa, but also led to immunosuppression in TME by regulating PDL1 and CD47. The proportion of CD8 + T cells in TME and among NK cells and monocytes was lower in LNM than in the primary lesion, while the opposite was true for Th and Treg cells. Furthermore, these immune cells in TME underwent transcriptional reprogramming, including CD8 + T subgroups of CCR7 + and IL7R+, as well as M2-like monocyte subgroups expressing tumor-associated signature genes, like CCR7, SGKI, and RPL31. Furthermore, STEAP4+, ADGRF5 + and CXCR4+, and SRGNC + fibroblast subgroups were closely related to tumor progression, tumor metabolism, and immunosuppression, indicating their contributions in PCa metastasis. Meanwhile, The presence of CXCR4 + Fibroblasts in PCa was confirmed by polychromatic immunofluorescence.ConclusionsThe significant heterogeneity of luminal, immune, and interstitial cells in PCa LNM may not only directly contribute to tumor progression, but also indirectly result in TME immunosuppression, which may be the cause of metastasis in PCa and in which MYC played an role.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

41116_2023_36_Article_IEq374.gif

Fig. 5

41116_2023_36_Article_IEq372.gif

41116_2023_36_Article_IEq370.gif

41116_2023_36_Article_IEq368.gif

41116_2023_36_Article_IEq366.gif

41116_2023_36_Article_IEq364.gif

Fig. 4

41116_2023_36_Article_IEq359.gif

41116_2023_36_Article_IEq358.gif

Fig. 3

41116_2023_36_Article_IEq347.gif

Fig. 4

41116_2023_36_Article_IEq322.gif

41116_2023_36_Article_IEq313.gif

41116_2023_36_Article_IEq304.gif

41116_2023_36_Article_IEq295.gif

41116_2023_36_Article_IEq285.gif

Fig. 2

41116_2023_36_Article_IEq267.gif

Fig. 1

41116_2023_36_Article_IEq255.gif

41116_2023_36_Article_IEq242.gif

41116_2023_36_Article_IEq227.gif

41116_2023_36_Article_IEq214.gif

41116_2023_36_Article_IEq205.gif

41116_2023_36_Article_IEq180.gif

41116_2023_36_Article_IEq170.gif

41116_2023_36_Article_IEq119.gif