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Single-cell Analysis Reveals Inter- and Intratumour Heterogeneity in Metastatic Breast Cancer.
Baptiste Hamelin1, Milan M S Obradović1,2,3, Atul Sethi1,2,3,4
1Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.
Journal of Mammary Gland Biology and Neoplasia
|December 8, 2023
Summary
Metastasis in breast cancer involves cells transitioning between epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) states, forming partial EMT phenotypes. Key transcription factors drive these changes, offering insights into cancer spread.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Metastasis is the primary cause of breast cancer mortality.
- Cancer cell plasticity and heterogeneity are crucial for metastasis, but mechanisms are unclear.
- Colonization is a critical, poorly understood step in the metastatic cascade.
Purpose of the Study:
- To identify molecular mechanisms driving metastasis during the colonization phase.
- To investigate cell states and transcriptional regulation in breast cancer metastasis.
Main Methods:
- Single-cell RNA sequencing (scRNA-Seq) was performed on patient-derived xenograft tumors and matched lung metastases.
- Data were corrected for cell cycle and percentage of detected genes (PDG).
- Gene-set enrichment analysis and differential gene expression analysis were conducted.
Main Results:
- Three distinct cell states were identified in both tumors and metastases.
- Two states showed enrichment for proliferation and invasion, linked to partial epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transition phenotypes.
- Common partial EMT transcription factors (TFs), including ZNF750, OVOL2, TP63, TFAP2C, and HEY2, were identified as key regulators.
Conclusions:
- Partial EMT phenotypes, regulated by specific TFs, are crucial for breast cancer metastasis.
- These findings reveal common molecular features across different breast cancer metastasis models.
- The study underscores interpatient heterogeneity while identifying conserved mechanisms in metastatic breast cancer cells.
