Department of Urology, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Department of Urology, West China Hospital of Sichuan University, Chengdu 610041, China.
Cell Signal. 2024 Dec;124:111453. doi: 10.1016/j.cellsig.2024.111453. Epub 2024 Oct 2.
Tumor-associated macrophages (TAMs) play an important role in the recurrence and progression of clear cell renal cell carcinoma (ccRCC). However, the specified mechanism has not been elucidated.
Single-cell and transcriptome analysis were applied to characterize the heterogeneity of TAMs. SCENIC would infer regulators of different subsets of TAMs. The CellChat algorithm was used to infer macrophage-tumor interaction networks, whereas pseudo-time traces were used to parse cell evolution and dynamics.
In this study, single-cell transcriptomic data of ccRCC were analyzed. Notably, the macrophages were clustered to select the cluster with a tendency toward M2-type TAM, which has an impact on the occurrence and metastasis of ccRCC. This macrophage cluster was defined as "TAM2". And this study revealed that TCF7L2 as a potential transcription factor regulating TAM2 transcriptional heterogeneity and differentiation. Pseudotime traces showed TCF7L2 trajectories during TAM2 cell cluster development. In addition, the results of cell interaction showed that TAM2 had the highest number and strength of interactions with cancer cells and endothelial cells. In vitro experiments, this study found that TCF7L2 was highly expressed in TAMs and promoted the polarization of macrophages to M2-type macrophages. And then overexpression of TCF7L2 in macrophages markedly promoted ccRCC invasion and proliferation.
TCF7L2 could play a key role in the progression of ccRCC via enhancing TAMs recruitment and M2-type polarization.
肿瘤相关巨噬细胞（TAMs）在透明细胞肾细胞癌（ccRCC）的复发和进展中起着重要作用。然而，具体的机制尚未阐明。
应用单细胞和转录组分析来描绘 TAMs 的异质性。SCENIC 将推断不同 TAM 亚群的调节因子。CellChat 算法用于推断巨噬细胞-肿瘤相互作用网络，而伪时间轨迹用于解析细胞进化和动态。
本研究分析了 ccRCC 的单细胞转录组数据。值得注意的是，对巨噬细胞进行聚类以选择倾向于 M2 型 TAM 的簇，这对 ccRCC 的发生和转移有影响。这个巨噬细胞簇被定义为“TAM2”。本研究揭示了 TCF7L2 作为调节 TAM2 转录异质性和分化的潜在转录因子。伪时间轨迹显示了 TCF7L2 在 TAM2 细胞簇发育过程中的轨迹。此外，细胞相互作用的结果表明，TAM2 与癌细胞和内皮细胞的相互作用数量最多，强度最大。在体外实验中，本研究发现 TCF7L2 在 TAMs 中高表达，并促进巨噬细胞向 M2 型极化。然后，TCF7L2 在巨噬细胞中的过表达显著促进了 ccRCC 的侵袭和增殖。
TCF7L2 可以通过增强 TAMs 的募集和 M2 型极化在 ccRCC 的进展中发挥关键作用。
