Xin Shiyong, Liu Xiang, Li Ziyao, Sun Xianchao, Wang Rong, Zhang Zhenhua, Feng Xinwei, Jin Liang, Li Weiyi, Tang Chaozhi, Mei Wangli, Cao Qiong, Wang Haojie, Zhang Jianguo, Feng Lijin, Ye Lin
Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China.
Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.
Exp Hematol Oncol. 2023 May 23;12(1):49. doi: 10.1186/s40164-023-00407-0.
BACKGROUND: Metastasis 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. METHODS: A 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. RESULTS: The 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. CONCLUSIONS: The 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.
背景：转移是前列腺癌（PCa）患者疾病进展导致死亡的关键因素。然而，其机制仍不清楚。我们旨在通过单细胞RNA测序（scRNA-seq）分析PCa肿瘤微环境（TME）的异质性，以探索淋巴结转移（LNM）的机制。 方法：从4个PCa组织样本中获取32766个细胞进行scRNA-seq，进行注释和分组。对每个细胞亚组进行InferCNV、基因集变异分析（GSVA）、差异表达基因（DEG）功能富集分析、轨迹分析、细胞间网络评估和转录因子分析。此外，针对管腔细胞亚组和CXCR4+成纤维细胞亚组进行了验证实验。 结果：结果显示，LNM中仅存在EEF2+和FOLH1+管腔亚组，它们出现在管腔细胞分化的初始阶段，验证实验证实了这一点。MYC通路在EEF2+和FOLH1+管腔亚组中富集，且MYC与PCa LNM相关。此外，MYC不仅促进PCa的进展，还通过调节程序性死亡配体1（PDL1）和CD47导致TME中的免疫抑制。LNM中TME内以及自然杀伤（NK）细胞和单核细胞中CD8+T细胞的比例低于原发灶，而辅助性T细胞（Th）和调节性T细胞（Treg）则相反。此外，TME中的这些免疫细胞经历了转录重编程，包括CCR7+和白细胞介素7受体（IL7R+）的CD8+T亚组，以及表达肿瘤相关特征基因（如CCR7、丝氨酸/苏氨酸激酶1（SGKI）和核糖体蛋白L31（RPL31））的M2样单核细胞亚组。此外，STEAP4+、黏附G蛋白偶联受体F5（ADGRF5）+和CXCR4+以及富含亮氨酸重复序列的G蛋白偶联受体N家族成员1（SRGNC）+成纤维细胞亚组与肿瘤进展、肿瘤代谢和免疫抑制密切相关，表明它们在PCa转移中的作用。同时，通过多色免疫荧光证实了PCa中CXCR4+成纤维细胞的存在。 结论：PCa LNM中管腔、免疫和间质细胞的显著异质性不仅可能直接促进肿瘤进展，还可能间接导致TME免疫抑制，这可能是PCa转移的原因，且MYC在其中发挥了作用。
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