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Updated: May 8, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Clonal Lineage Tracing Reveals Distinct Invasive Subpopulations in Triple-Negative Breast Cancer
Carolina De Santiago1, Andrea L Gardner1, Patrik Parker1
1Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas, USA.
Abstract:
Metastatic dissemination in triple-negative breast cancer (TNBC) arises from extensive intratumoral heterogeneity, yet the clonal and transcriptional programs that underlie invasive behavior remain poorly defined. The field lacks experimental systems capable of simultaneously tracking the clonal identity and transcriptional state of invasive subpopulations. Here, we apply a clonal lineage-tracing platform coupled with single-cell RNA sequencing to resolve how subpopulations contribute to invasion in a model of TNBC. We demonstrate that invasion is driven by a subset of recurrent clones, indicating the presence of pre-existing subpopulations intrinsically primed for migratory behavior. Transcriptomic profiling further reveals two transcriptomically distinct invasive cell states that remain stable across independent selections. Targeted perturbations suppress these dominant invasive programs but enable invasion by alternative rare clones, demonstrating compensatory clonal dynamics in response to selective pressure. Together these findings show that invasive potential arises from stable clonal programs and that heterogenous tumors maintain invasive capacity through clonal replacement. Clonally resolved single-cell profiling provides a framework for dissecting invasive heterogeneity and highlights the need for therapeutic strategies that account for clone-specific behaviors and the dynamic restructuring of tumor subpopulations.
Insights
Metastatic triple-negative breast cancer (TNBC) invasion is driven by specific, pre-existing clones with stable migratory programs. Tumor heterogeneity maintains invasion through compensatory clonal dynamics and replacement under selective pressure.
Area of Science:
- Oncology
- Cancer Biology
- Genomics
Background:
- Triple-negative breast cancer (TNBC) exhibits significant intratumoral heterogeneity.
- The clonal and transcriptional drivers of TNBC metastatic dissemination are not well understood.
- Existing experimental systems cannot simultaneously track clonal identity and transcriptional states of invasive cells.
Purpose of the Study:
- To investigate the clonal and transcriptional programs underlying invasion in TNBC.
- To develop and utilize an experimental system for simultaneous clonal and transcriptional profiling of invasive subpopulations.
- To understand how tumor heterogeneity contributes to metastatic dissemination in TNBC.
Main Methods:
- Application of a clonal lineage-tracing platform.
- Integration with single-cell RNA sequencing (scRNA-seq) for transcriptomic profiling.
- Development of a TNBC model system to study invasion.
Main Results:
- Invasion is driven by a subset of recurrent clones, suggesting pre-existing subpopulations primed for migration.
- Two distinct, stable transcriptomic invasive cell states were identified.
- Targeted suppression of dominant invasive programs led to compensatory invasion by alternative rare clones.
Conclusions:
- Invasive potential in TNBC is linked to stable clonal programs.
- Tumor heterogeneity sustains invasive capacity via clonal replacement and compensatory dynamics.
- Clonally resolved single-cell profiling offers a framework for dissecting invasive heterogeneity and informs therapeutic strategies targeting clone-specific behaviors.
