Cell Stress (Mar 2024)

MiR-200c reprograms fibroblasts to recapitulate the phenotype of CAFs in breast cancer progression

  • Zhao Lin,
  • Megan E. Roche,
  • Víctor Díaz-Barros,
  • Marina Domingo-Vidal,
  • Diana Whitaker-Menezes,
  • Madalina Tuluc,
  • Guldeep Uppal,
  • Jaime Caro,
  • Joseph M. Curry,
  • Ubaldo Martinez-Outschoorn

DOI
https://doi.org/10.15698/cst2024.03.293
Journal volume & issue
Vol. 8
pp. 1 – 20

Abstract

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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.

Keywords