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Myeloid Mir34a suppresses colitis-associated colon cancer: characterization of mediators by single-cell RNA
Janine König1, Matjaz Rokavec1, Meryem Gülfem Öner-Ziegler1
1Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, D-80337, Munich, Germany.
Abstract:
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.
Insights
Deleting microRNA 34a (Mir34a) in myeloid cells promotes colitis-associated colorectal cancer (CAC) growth and invasion in mice. This occurs by increasing M2-like macrophages and their migration, highlighting myeloid Mir34a as a tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- The p53-inducible microRNA 34a (Mir34a) plays a role in tumor suppression.
- The tumor microenvironment (TME) influences cancer progression.
- Colitis-associated colorectal cancers (CACs) are a significant health concern.
Purpose of the Study:
- To investigate the role of myeloid-specific Mir34a deletion in CAC development.
- To characterize the impact of Mir34a deficiency on immune cells within the TME.
- To identify potential therapeutic targets for CAC treatment.
Main Methods:
- Mice with myeloid-specific Mir34a deletion were used to study CAC.
- Single-cell RNA sequencing (scRNA-Seq) was employed to analyze immune cell populations.
- Macrophage phenotypes, migration, and gene expression were assessed.
- The role of Colony-Stimulating Factor 1 Receptor (Csf1r) was evaluated.
Main Results:
- Deletion of Mir34a in myeloid cells increased the number and invasion of CACs.
- Specific macrophage subtypes, including M2-like macrophages, were enriched.
- Mir34a-deficient macrophages exhibited enhanced migration and M2 polarization.
- Inhibition of Csf1r reduced CAC burden and invasion.
- A novel inflammatory CAC cell subtype with epithelial and macrophage markers was identified.
Conclusions:
- Myeloid Mir34a acts as a tumor suppressor in CAC by maintaining macrophages in an M1-like state.
- Repression of Mir34a targets, such as Csf1r, is a key mechanism.
- Targeting myeloid Mir34a or its downstream effectors may offer new therapeutic strategies for CAC.
