Metabolic memory underlying minimal residual disease in breast cancer
Ksenija Radic Shechter1, Eleni Kafkia1,2, Katharina Zirngibl1,2
1European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Abstract:
Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer-related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi-omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small-molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence.
Insights
Minimal residual disease (MRD) cells in breast cancer exhibit increased glycolysis and urea cycle enzyme activity, offering new therapeutic targets. Targeting these metabolic vulnerabilities can prevent tumor recurrence after treatment.
Area of Science:
- Oncology
- Metabolic Engineering
- Epigenetics
Background:
- Tumor relapse from treatment-resistant cells, known as minimal residual disease (MRD), is a primary cause of breast cancer mortality.
- The molecular drivers of MRD malignancy remain poorly understood, hindering the development of effective post-treatment strategies.
Purpose of the Study:
- To elucidate the metabolic and regulatory characteristics of MRD cells.
- To identify potential therapeutic targets for preventing breast cancer recurrence.
Main Methods:
- Integrated multi-omics data analysis using a novel organoid system.
- Metabolic modeling to identify metabolic idiosyncrasies.
- Validation in mouse models and patient transcriptomic data.
- DNA methylation profiling.
Main Results:
- MRD cells display increased glycolysis and urea cycle enzyme activity, irrespective of proliferation status or oncogenic signaling.
- These metabolic features are conserved across organoid, mouse, and human patient data.
- Similarities in DNA methylation profiles were observed between tumor and residual cells.
- Elevated glycolysis in MRD is essential for survival and is targetable with specific inhibitors.
Conclusions:
- MRD cells possess a metabolic and epigenetic memory that contributes to their survival.
- Targeting the aberrant glycolysis in MRD presents a promising therapeutic strategy to prevent breast cancer recurrence.
- These findings open new avenues for post-treatment care in breast cancer management.
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