Longitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with
Danielle C Croucher1,2, Laura M Richards1,2, Serges P Tsofack1
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Abstract:
Molecular programs that underlie precursor progression in multiple myeloma are incompletely understood. Here, we report a disease spectrum-spanning, single-cell analysis of the Vκ*MYC myeloma mouse model. Using samples obtained from mice with serologically undetectable disease, we identify malignant cells as early as 30 weeks of age and show that these tumours contain subclonal copy number variations that persist throughout progression. We detect intratumoural heterogeneity driven by transcriptional variability during active disease and show that subclonal expression programs are enriched at different times throughout early disease. We then show how one subclonal program related to GCN2 stress response is progressively activated during progression in myeloma patients. Finally, we use chemical and genetic perturbation of GCN2 in vitro to support this pathway as a therapeutic target in myeloma. These findings therefore present a model of precursor progression in Vκ*MYC mice, nominate an adaptive mechanism important for myeloma survival, and highlight the need for single-cell analyses to understand the biological underpinnings of disease progression.
Insights
This study reveals early malignant cell detection and subclonal evolution in multiple myeloma precursor progression using single-cell analysis. It identifies the GCN2 stress response pathway as a potential therapeutic target for myeloma.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The molecular mechanisms driving multiple myeloma precursor progression remain unclear.
- Understanding early disease development is crucial for effective therapeutic strategies.
Purpose of the Study:
- To investigate the molecular programs underlying precursor progression in multiple myeloma.
- To identify early malignant cell markers and adaptive survival mechanisms.
Main Methods:
- Single-cell RNA sequencing of the Vκ*MYC mouse model across disease spectrum.
- Analysis of subclonal copy number variations and transcriptional heterogeneity.
- In vitro chemical and genetic perturbation of the GCN2 pathway.
Main Results:
- Malignant cells identified as early as 30 weeks in Vκ*MYC mice.
- Subclonal copy number variations persist throughout disease progression.
- Intratumoural heterogeneity driven by transcriptional variability observed.
- GCN2 stress response pathway progressively activated in myeloma patients and validated as a therapeutic target.
Conclusions:
- Presents a model for precursor progression in Vκ*MYC mice.
- Nominates GCN2 pathway as a critical adaptive mechanism for myeloma survival.
- Highlights the importance of single-cell analyses for understanding myeloma progression.
