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
Affiliations
Zhao Lin
Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Megan E. Roche
Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Víctor Díaz-Barros
Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Marina Domingo-Vidal
Immunology, Microenvironment & Metastasis Program, Wistar Institute, Philadelphia, Pennsylvania, USA.
Diana Whitaker-Menezes
Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Madalina Tuluc
Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Guldeep Uppal
Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Jaime Caro
Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Joseph M. Curry
Department of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Ubaldo Martinez-Outschoorn
Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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.
