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Updated: Nov 16, 2025
Development of a Larval Zebrafish Infection Model for Clostridioides difficile
Published on: February 14, 2020
Innate immune evasion revealed in a colorectal zebrafish xenograft model
Vanda Póvoa1, Cátia Rebelo de Almeida1, Mariana Maia-Gil1
1Champalimaud Centre for the Unknown, Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal.
Abstract:
Cancer immunoediting is a dynamic process of crosstalk between tumor cells and the immune system. Herein, we explore the fast zebrafish xenograft model to investigate the innate immune contribution to this process. Using multiple breast and colorectal cancer cell lines and zAvatars, we find that some are cleared (regressors) while others engraft (progressors) in zebrafish xenografts. We focus on two human colorectal cancer cells derived from the same patient that show contrasting engraftment/clearance profiles. Using polyclonal xenografts to mimic intra-tumor heterogeneity, we demonstrate that SW620_progressors can block clearance of SW480_regressors. SW480_regressors recruit macrophages and neutrophils more efficiently than SW620_progressors; SW620_progressors however, modulate macrophages towards a pro-tumoral phenotype. Genetic and chemical suppression of myeloid cells indicates that macrophages and neutrophils play a crucial role in clearance. Single-cell-transcriptome analysis shows a fast subclonal selection, with clearance of regressor subclones associated with IFN/Notch signaling and escaper-expanded subclones with enrichment of IL10 pathway. Overall, our work opens the possibility of using zebrafish xenografts as living biomarkers of the tumor microenvironment.
Insights
Zebrafish xenografts reveal how cancer cells interact with the immune system. Certain cancer cells are cleared, while others grow, highlighting the potential of zebrafish models for understanding tumor microenvironments.
Area of Science:
- Immunology
- Oncology
- Developmental Biology
Background:
- Cancer immunoediting involves complex interactions between tumor cells and the immune system.
- Understanding the innate immune system's role in this process is crucial for developing new cancer therapies.
Purpose of the Study:
- To investigate the innate immune contribution to cancer immunoediting using a zebrafish xenograft model.
- To explore the potential of zebrafish xenografts as biomarkers for the tumor microenvironment.
Main Methods:
- Utilized zebrafish xenografts with various human breast and colorectal cancer cell lines (zAvatars).
- Employed polyclonal xenografts to model intra-tumor heterogeneity.
- Performed genetic and chemical suppression of myeloid cells.
- Conducted single-cell transcriptome analysis.
Main Results:
- Identified distinct cancer cell behaviors: clearance (regressors) versus engraftment (progressors) in zebrafish.
- Demonstrated that progressor cells can inhibit the clearance of regressor cells.
- Showed that macrophages and neutrophils are critical for cancer cell clearance.
- Observed subclonal selection linked to specific signaling pathways (IFN/Notch for clearance, IL10 for escape).
Conclusions:
- Zebrafish xenografts effectively model cancer immunoediting dynamics and innate immune responses.
- Macrophages and neutrophils play a vital role in eliminating tumor cells.
- Zebrafish xenografts show promise as living biomarkers for evaluating the tumor microenvironment and predicting treatment responses.
