Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity
- Tel Aviv University, Israel
- The Weizmann Institute of Science, Israel
- Sheba Medical Center, Israel
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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE128999.
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RNA-seq profiling of fibroblasts isolated from two distinct lung metastases stages and from normal lungsNCBI Gene Expression Omnibus, GSE128999.
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Gene Expression Profiling of Tumor Microenvironment during Breast Cancer ProgressionNCBI Gene Expression Omnibus, GSE14548.
Article and author information
Author details
Funding
H2020 European Research Council (637069 MetCAF)
- Ophir Shani
- Yael Raz
Israel Science Foundation (1060/18)
- Ophir Shani
- Yael Raz
- Noam Cohen
- Neta Erez
The Emerson Collective
- Ophir Shani
- Lea Monteran
- Neta Erez
Israel Cancer Association
- Ophir Shani
- Neta Erez
Israel Cancer Research Fund (Project Grant)
- Ophir Shani
- Yael Raz
- Lea Monteran
- Neta Erez
Breast Cancer Research Foundation
- Or Megides
- Ilan Tsarfaty
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Wilbert Zwart, Netherlands Cancer Institute, Netherlands
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Tel Aviv University. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols #: 01-18-035, M-13-026, 01-17-024) of the Tel Aviv University.
Human subjects: Human patient samples were collected and processed at the Sheba Medical Center, Israel under an approved institutional review board (IRB) (3112-16).
Version history
- Received: July 6, 2020
- Accepted: June 24, 2021
- Accepted Manuscript published: June 25, 2021 (version 1)
- Version of Record published: July 5, 2021 (version 2)
Copyright
© 2021, Shani et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity
eLife 10:e60745.
https://doi.org/10.7554/eLife.60745
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