Modeling tumor relapse using proliferation tracing and ablation transgenic mouse.

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Tumor relapse presents a significant challenge in cancer therapy.
• Preclinical models that accurately mimic human tumor relapse are essential for developing effective treatments.

Purpose of the Study:

• To develop and utilize a novel genetic model for tracing and ablating proliferating cells in a spontaneous murine breast cancer model.
• To investigate the cellular and molecular changes associated with tumor relapse.

Main Methods:

• Employed a dual recombinase-mediated genetic system for proliferation tracing and ablation in polyomavirus middle T antigen (PyMT)-induced breast cancer.
• Utilized single-cell RNA sequencing (scRNA-seq) to compare primary and relapsed tumor ecosystems.

Main Results:

• Acute ablation of proliferating cells led to tumor shrinkage, followed by relapse from residual low-cycling cells.
• Relapsed tumors showed increased cancer stem cells and pro-tumor γδ T cells.
• Myeloid cells in relapsed tumors exhibited co-expression of Spp1 and Vegfa, correlating with poor patient outcomes.

Conclusions:

• The developed proliferation tracing and ablation model effectively emulates chemotherapy targeting proliferating cells.
• This model serves as a valuable tool for testing novel therapeutic strategies against relapsed tumors.
• Findings highlight key cellular changes in relapsed breast cancer, offering insights into therapeutic resistance.