MiR-145 reprogramming facilitates fibrotic trajectory in the tumor microenvironment
- 1Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
- 2Department of Otolaryngology, Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
Abstract
The fibrotic subtype of the tumor microenvironment characterized by epithelial-mesenchymal transition, fibrosis, angiogenesis and immune exclusion, predicts poor outcomes across diverse malignancies, yet the role of miR-145 in this context remains unexplored. Leveraging The Cancer Genome Atlas head and neck squamous cell carcinoma (HNSCC) and breast cancer (BRCA) databases, we demonstrate that miR-145 reprogramming recapitulates a noninflamed fibrotic phenotype with immune exclusion. In high miR-145 tumors, EMT programs persist alongside abundant cancer-associated fibroblasts, matrix remodeling and angiogenesis, with upregulation of NOTCH, TGF-β, myogenesis, hypoxia, Hedgehog, and Wnt/β-catenin signaling and downregulation of interferon-γ and JAK–STAT pathways. Our findings illustrate that cancer–stromal juxtacrine interactions activate NOTCH signaling, forming a positive feedback loop that amplifies miR-145 expression and is reinforced by miR-145 promoter hypomethylation. High miR-145 promotes autophagy and mitochondrial oxidative phosphorylation (OXPHOS) metabolism in cancer cells, with GAPDH serving as a central hub linking metabolism, noninflamed immune modulation, and poor clinical outcomes. In vivo, high miR-145 carcinoma cells co-engrafted with fibroblasts drive tumor growth through enhanced metabolism, angiogenesis and immune evasion. This study establishes miR-145 as a driver and biomarker of the fibrotic tumor microenvironment to better inform future cancer therapy strategies.
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BibTeX
@article{lin2026mir145,
title = {{MiR-145 reprogramming facilitates fibrotic trajectory in the tumor microenvironment}},
author = {Zhao Lin and Megan Bennett and Patrick Tassone and Joseph M. Curry and Ubaldo Martinez-Outschoorn},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1850756},
url = {https://doi.org/10.3389/fcell.2026.1850756},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - MiR-145 reprogramming facilitates fibrotic trajectory in the tumor microenvironment
AU - Zhao Lin
AU - Megan Bennett
AU - Patrick Tassone
AU - Joseph M. Curry
AU - Ubaldo Martinez-Outschoorn
PY - 2026
DA - 2026/10/19
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1850756
UR - https://doi.org/10.3389/fcell.2026.1850756
AB - The fibrotic subtype of the tumor microenvironment characterized by epithelial-mesenchymal transition, fibrosis, angiogenesis and immune exclusion, predicts poor outcomes across diverse malignancies, yet the role of miR-145 in this context remains unexplored. Leveraging The Cancer Genome Atlas head and neck squamous cell carcinoma (HNSCC) and breast cancer (BRCA) databases, we demonstrate that miR-145 reprogramming recapitulates a noninflamed fibrotic phenotype with immune exclusion. In high miR-145 tumors, EMT programs persist alongside abundant cancer-associated fibroblasts, matrix remodeling and angiogenesis, with upregulation of NOTCH, TGF-β, myogenesis, hypoxia, Hedgehog, and Wnt/β-catenin signaling and downregulation of interferon-γ and JAK–STAT pathways. Our findings illustrate that cancer–stromal juxtacrine interactions activate NOTCH signaling, forming a positive feedback loop that amplifies miR-145 expression and is reinforced by miR-145 promoter hypomethylation. High miR-145 promotes autophagy and mitochondrial oxidative phosphorylation (OXPHOS) metabolism in cancer cells, with GAPDH serving as a central hub linking metabolism, noninflamed immune modulation, and poor clinical outcomes. In vivo, high miR-145 carcinoma cells co-engrafted with fibroblasts drive tumor growth through enhanced metabolism, angiogenesis and immune evasion. This study establishes miR-145 as a driver and biomarker of the fibrotic tumor microenvironment to better inform future cancer therapy strategies.
SN - 2296-634X
ER -