König Janine, Rokavec Matjaz, Öner-Ziegler Meryem Gülfem, Fei Ye, Hermeking Heiko
Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, D-80337, Munich, Germany.
German Cancer Consortium (DKTK), Partner site Munich, D-80336, Munich, Germany.
Cell Death Differ. 2025 Feb;32(2):225-241. doi: 10.1038/s41418-024-01380-9. Epub 2024 Oct 18.
We have previously shown that general deletion of the gene encoding the p53-inducible Mir34a microRNA enhances the number and invasion of colitis-associated colorectal cancers (CACs) in mice. Since the p53-pathway has been implicated in tumor-suppression mediated by cells in the tumor microenvironment (TME) we deleted Mir34a in myeloid cells and characterized CACs in these with scRNA-Seq (single cell RNA sequencing). This revealed an increase in specific macrophage subtypes, such as Cdk8 macrophages and Mrc1, M2-like macrophages. The latter displayed elevated expression of 21 known Mir34a target mRNAs, including Csf1r, Axl, Foxp1, Ccr1, Nampt, and Tgfbr2, and 32 predicted Mir34a target mRNAs. Furthermore, Mir34a-deficient BMDMs showed enhanced migration, elevated expression of Csf1r and a shift towards M2-like polarization when compared to Mir34a-proficient BMDMs. Concomitant deletion of Csf1r or treatment with a Csf1r inhibitor reduced the CAC burden and invasion in these mice. Notably, loss of myeloid Mir34a function resulted in a prominent, inflammatory CAC cell subtype, which displayed epithelial and macrophage markers. These cells displayed high levels of the EMT transcription factor Zeb2 and may therefore enhance the invasiveness of CACs. Taken together, our results provide in vivo evidence for a tumor suppressive role of myeloid Mir34a in CACs which is, at least in part, mediated by maintaining macrophages in an M1-like state via repression of Mir34a targets, such as Csf1r. Collectively, these findings may serve to identify new therapeutic targets and approaches for treatment of CAC.
我们之前已经表明，编码p53诱导型Mir34a微小RNA的基因的整体缺失会增加小鼠中结肠炎相关结直肠癌（CAC）的数量并增强其侵袭性。由于p53通路与肿瘤微环境（TME）中细胞介导的肿瘤抑制有关，我们在髓系细胞中删除了Mir34a，并通过单细胞RNA测序（scRNA-Seq）对这些细胞中的CAC进行了表征。这揭示了特定巨噬细胞亚型的增加，如Cdk8巨噬细胞和Mrc1、M2样巨噬细胞。后者显示出21种已知的Mir34a靶标mRNA的表达升高，包括Csf1r、Axl、Foxp1、Ccr1、Nampt和Tgfbr2，以及32种预测的Mir34a靶标mRNA。此外，与具有Mir34a的骨髓来源的巨噬细胞（BMDM）相比，缺乏Mir34a的BMDM显示出增强的迁移能力、Csf1r表达升高以及向M2样极化的转变。同时删除Csf1r或用Csf1r抑制剂处理可减轻这些小鼠的CAC负担和侵袭性。值得注意的是，髓系Mir34a功能的丧失导致了一种突出的、炎症性的CAC细胞亚型，其显示上皮和巨噬细胞标志物。这些细胞显示出高水平的上皮-间质转化（EMT）转录因子Zeb2，因此可能增强CAC的侵袭性。综上所述，我们的结果为髓系Mir34a在CAC中的肿瘤抑制作用提供了体内证据，这至少部分是通过抑制Mir34a靶标（如Csf1r）来维持巨噬细胞处于M1样状态介导的。总的来说，这些发现可能有助于识别治疗CAC的新治疗靶点和方法。
