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, Ruth Scherz-Shouval, Iris Barshack, Ilan Tsarfaty, Neta Erez

Research output: Contribution to journalArticlepeer-review

Abstract

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 knowledge-based 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.

Original languageEnglish
Article numbere60745
JournaleLife
Volume10
DOIs
StatePublished - Jun 2021

Keywords

  • Breast cancer
  • Fibroblasts
  • Metastasis
  • Microenvironment

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