Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity

Ophir Shani, Yael Raz, Lea Monteran, Ye'ela Scharff, Oshrat Levi-Galibov, Or Megides, Hila Shacham, Noam Cohen, Dana Silverbush, Camilla Avivi, Roded Sharan, Asaf Madi (+4 others)
2021 eLife  
Mortality from breast cancer is almost exclusively a result of tumor metastasis, and lungs are one of the main metastatic sites. Cancer-associated fibroblasts (CAFs) are prominent players in the microenvironment of breast cancer. However, their role in the metastatic niche is largely unknown. In this study, we profiled the transcriptional co-evolution of lung fibroblasts isolated from transgenic mice at defined stage-specific time points of metastases formation. Employing multiple
more » ... d platforms of data analysis provided powerful insights on functional and temporal regulation of the transcriptome of fibroblasts. We demonstrate that fibroblasts in lung metastases are transcriptionally dynamic and plastic, and reveal stage-specific gene signatures that imply functional tasks, including extracellular matrix remodeling, stress response and shaping the inflammatory microenvironment. Furthermore, we identified Myc as a central regulator of fibroblast rewiring and found that stromal upregulation of Myc transcriptional networks is associated with disease progression in human breast cancer.
doi:10.7554/elife.60745 pmid:34169837 pmcid:PMC8257251 fatcat:ohkhgkxwxzepxct5ton52i4uhq