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

Authors:

Zhao Lin1, Megan E. Roche1, Víctor Díaz-Barros1, Marina Domingo-Vidal2, Diana Whitaker-Menezes1, Madalina Tuluc3, Guldeep Uppal3, Jaime Caro4, Joseph M. Curry5 and Ubaldo Martinez-Outschoorn1
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Affiliations:

1 Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

2 Immunology, Microenvironment & Metastasis Program, Wistar Institute, Philadelphia, Pennsylvania, USA.

3 Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

4 Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

5 Department of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

Keywords: 

oxidative stress, miR-200c, chromatin modification, senescence, NFκB-HIF signaling, cancer immunology and immunotherapy.

Abbreviations:

BRCA – breast cancer;

CAF – cancer-associated fibroblast;

EMP – epithelial-mesenchymal plasticity;

EMT – epithelial-to-mesenchymal transition;

miR – microRNA;

MET – mesenchymal-to-epithelial transition;

ROS – reactive oxygen species;

SASP – senescence-associated secretory phenotype;

ScRNASeq – single cell RNA sequencing;

TME – tumor microenvironment.

Corresponding Author(s):

Ubaldo Martinez-Outschoorn, Thomas Jefferson University, Sidney Kimmel Cancer Center, 233 S. 10th Street Suite 909 Philadelphia PA 19107; Telephone: 215-955-9774; ubaldo.martinez-outschoorn@jefferson.edu

Conflict of interest statement:

The authors declare no competing interests.

Please cite this article as:

Zhao Lin, Megan Roche, Victor Diaz Barros, Marina Domingo-Vidal, Diana Whitaker-Menezes, Madalina Tuluc, Guldeep Uppal, Jaime Caro, Joseph M Curry and Ubaldo Martinez-Outschoorn (2024). MiR-200c reprograms fibroblasts to recapitulate the phenotype of CAFs in breast cancer progression. Cell Stress 8: 1-20. doi: 10.15698/cst2024.02.293

© 2024 Lin et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

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.