Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces a senescent phenotype. This pro-tumorigenic profile in CAFs fosters carcinoma cell resistance to apoptosis, proliferation and immunosuppression, leading to primary tumor growth, metastases, and resistance to immuno-chemotherapy. Conversely, miR-200c inhibition in fibroblasts restrains tumor growth with abated oxidative stress and an anti-tumorigenic immune environment. This work determines the mechanisms by which MET in CAFs via miR-200c transcriptional enrichment with DNA demethylation triggered by oxidative stress promotes cancer progression. CAFs undergoing MET trans-differentiation and senescence coordinate heterotypic signaling that may be targeted as an anti-cancer strategy.
Keyphrases
- cell proliferation
- oxidative stress
- long non coding rna
- long noncoding rna
- poor prognosis
- rna seq
- single cell
- signaling pathway
- endothelial cells
- stem cells
- dna damage
- extracellular matrix
- tyrosine kinase
- clinical trial
- ischemia reperfusion injury
- randomized controlled trial
- pi k akt
- mesenchymal stem cells
- drug delivery
- papillary thyroid
- mass spectrometry
- lps induced
- inflammatory response
- young adults
- induced pluripotent stem cells
- heat shock
- phase iii
- study protocol
- double blind