METTL3-mediated m6A methylation regulates ovarian cancer progression by recruiting myeloid-derived suppressor cells
Bibliographic record
Abstract
Abstract Background Ovarian cancer typically develops an immunosuppressive microenvironment with excess recruitment of various leukocytes. The infiltrated leukocytes often exhibit protumor or anti-tumor activity depending on the surrounding signals in the microenvironment. Dysregulated m6A level is associated with cancer progression by influencing intrinsic oncogenic pathways in tumor cells. However, the role of m6A in regulating host immune cell function during anti-tumor immunity still needs to be fully investigated. Methods We firstly generated the myeloid-specific Mettl3 gene knockout mice by using the CreLoxP system in which Mettl3fl/fl mice were crossed with Lyz2-Cre +/+ mice. ID8 were injected intraperitoneally into WT and Mettl3-cKO mice used as a syngeneic mouse model for evaluation of epithelial OC growth. Next, we analyzed the compositions of different immune cell populations in the TME by flow cytometry and single cell sequenencing. Furthurmore, we investigate why Mettl3-cKO mice recruit more Gr-1+ MDSCs in the peritoneal cavity after OC cells implantation by ELISA based screening of chemokines and cytokines in peritoneal lavage and serum. Lastly, we specify the role of METTL3 in regulating IL-1β secretion and inflammasome activation in Bone marrow-derived macrophages (BMDMs) cocultured with either ID8 cell by using immunoblotting and ELISA. Results In this study, we aimed to investigate the role of METTL3, a catalytic subunit of the methyltransferase complex, in regulating host immune cell response against ovarian cancer. We found that ovarian cancer cell growth was enhanced in Mettl3-deficient mice. A shift of decreased M1 polarization to increased M2 polarization of macrophages during ovarian cancer progression was observed. Furthermore, Mettl3 depletion in myeloid lineage cells facilitates the recruitment of Gr-1 + MDSCs by increased secretion of CCL2 and CXCL2. Interestingly, we demonstrated that Mettl3 deficiency enhances IL-1β secretion induced by viable ID8 cells but not cell lysates independent of inflammasome activation and cell death. Therefore, in tumor-bearing mice, ovarian cancer cells trigger a slight inflammatory response with a low-to-moderate secretion of pro-inflammatory cytokines and chemokines. Conclusion This study provides new insights into METTL3-mediated m6A methylation in regulating host immune response against ovarian cancer.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".