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Zebrafish Avatars: Toward Functional Precision Medicine in Low-Grade Serous Ovarian Cancer
Charlotte Fieuws1,2,3, Jan Willem Bek1,2,3, Bram Parton1,2,3
1Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
Abstract:
Ovarian cancer (OC) is an umbrella term for cancerous malignancies affecting the ovaries, yet treatment options for all subtypes are predominantly derived from high-grade serous ovarian cancer, the largest subgroup. The concept of "functional precision medicine" involves gaining personalized insights on therapy choice, based on direct exposure of patient tissues to drugs. This especially holds promise for rare subtypes like low-grade serous ovarian cancer (LGSOC). This study aims to establish an in vivo model for LGSOC using zebrafish embryos, comparing treatment responses previously observed in mouse PDX models, cell lines and 3D tumor models. To address this goal, a well-characterized patient-derived LGSOC cell line with the KRAS mutation c.35 G>T (p.(Gly12Val)) was used. Fluorescently labeled tumor cells were injected into the perivitelline space of 2 days' post-fertilization zebrafish embryos. At 1 day post-injection, xenografts were assessed for tumor size, followed by random allocation into treatment groups with trametinib, luminespib and trametinib + luminespib. Subsequently, xenografts were euthanized and analyzed for apoptosis and proliferation by confocal microscopy. Tumor cells formed compact tumor masses (n = 84) in vivo, with clear Ki67 staining, indicating proliferation. Zebrafish xenografts exhibited sensitivity to trametinib and luminespib, individually or combined, within a two-week period, establishing them as a rapid and complementary tool to existing in vitro and in vivo models for evaluating targeted therapies in LGSOC.
Insights
Zebrafish embryos provide a rapid model for low-grade serous ovarian cancer (LGSOC) drug testing. This study shows zebrafish xenografts respond to targeted therapies, offering a new tool for functional precision medicine in rare ovarian cancers.
Area of Science:
- Oncology
- Zebrafish models
- Functional precision medicine
Background:
- Ovarian cancer (OC) treatments primarily target high-grade serous subtypes, leaving rare subtypes like low-grade serous ovarian cancer (LGSOC) underserved.
- Functional precision medicine, using direct drug exposure on patient tissues, offers personalized treatment insights, particularly for rare cancers.
- Existing LGSOC models (mouse PDX, cell lines, 3D cultures) have limitations in speed and direct patient relevance.
Purpose of the Study:
- To establish and validate a zebrafish embryo in vivo model for low-grade serous ovarian cancer (LGSOC).
- To compare drug treatment responses in the zebrafish model with existing LGSOC models.
- To assess the utility of zebrafish xenografts for evaluating targeted therapies in LGSOC.
Main Methods:
- A patient-derived LGSOC cell line with a KRAS mutation was fluorescently labeled and injected into zebrafish embryos.
- Tumor xenografts were established and assessed for size, proliferation (Ki67), and apoptosis.
- Zebrafish xenografts were treated with trametinib, luminespib, or a combination, and responses were analyzed.
Main Results:
- Zebrafish embryos successfully developed compact LGSOC tumor xenografts with detectable proliferation.
- The zebrafish xenografts demonstrated sensitivity to trametinib and luminespib, both individually and in combination.
- Treatment responses were observed within a two-week timeframe.
Conclusions:
- Zebrafish embryos serve as a rapid and effective in vivo model for LGSOC.
- This model complements existing LGSOC research tools for evaluating targeted therapies.
- The findings support the use of zebrafish xenografts in functional precision medicine for LGSOC.
