Man’s Best Friend – Solving the Dog Epigenome To Advance Human Oncology

The field of human oncology has made significant advances in recent years, thanks to the Human Genome Project and the extensive datasets generated by the Encyclopedia of DNA Elements (ENCODE) consortium. Similar levels of canine-specific data will be pivotal to enabling comparative medicine strategies, since tumors from domesticated dogs hold great potential as naturally occurring, valuable cancer models in translational research. This article discusses how the culture of canine-derived organoid lines can be used to make meaningful observations in the emerging field of comparative oncology, prompting the next revolution in animal and human cancer studies.

Closing the epigenomic divide

Canine tumors provide an excellent comparative oncology model due to their spontaneous occurrence, similarity to human tumors and shared environmental exposures. Dogs and humans can be exposed to similar external factors – including toxins, viruses and pollution – that can lead to epigenetic alterations, metabolic changes and immune-related changes, with the potential to cause cancer in both species. Research that investigates uncontrolled masses in companion animals can unravel the complexities of cancer pathogenesis in both animals and humans.

The field of human cancer research has been transformed by the wealth of next-generation sequencing (NGS) data, but veterinary medicine lacks an equivalent volume of canine-specific data. To bridge this gap, the Cho Lab at the College of Veterinary Medicine, Seoul National University, has undertaken pioneering work in mapping the epigenome of the domesticated dog.¹ This work comprises epigenomic studies that examine the chemical modifications to DNA and histone proteins that can influence gene expression, shedding light on the regulation of cancer-related genes. The research is helping to unlock valuable information to progress our understanding of comparative oncology by expanding the availability of canine NGS datasets, and this data is now being employed to investigate cancer biology using organoids.

The role of organoids in comparative oncology

Three-dimensional organoid cultures have emerged as a powerful tool for studying cancer development and treatment response, faithfully mimicking the architecture and functionality of real organs. Canine-derived organoids from tumor models exhibit remarkable similarities to their human counterparts, including histological features, gene expression patterns and responses to therapeutic agents. Organoids from various tumor sample types can be cultivated, including mammary gland tumors, osteosarcomas and melanomas. These canine-derived organoid cultures can be used to assess the efficacy of various treatments and identify potential biomarkers, contributing vital primary data for comparison with human organoids. Evaluating multiple treatment options in this way provides a valuable opportunity to optimize therapeutic strategies before clinical trials in human patients.

The importance of reliable cell culture management

Organoids are delicate cell structures that require gentle handling to prevent any loss of sample. Aspiration is a frequently repeated step throughout the course of organoid research for culture maintenance, sample extraction and NGS library preparation. The Cho Lab relies on the VACUSAFE safe aspiration system and VACUSIP portable aspiration system from INTEGRA Biosciences to enhance the control of aspiration activities compared to traditional alternatives (Figure 1). The finger-activated valve feature of INTEGRA’s VACUSAFE system provides sensitive control of the aspiration flow, with a choice of different vacuum intensities to further enhance the gentle handling of precious organoids. In addition, INTEGRA’s lightweight, portable VACUSIP aspiration system enables maximum comfort and flexibility throughout the laboratory, making it ideal for both cell culture maintenance and NGS workflows.

Figure 1: Borris D. Aldonza, Cho Lab, uses the INTEGRA VACUSAFE safe aspiration system for epigenomic research and organoid culture studies in comparative oncology. Credit: The College of Veterinary Medicine at Seoul National University.

Translational potential and therapeutic discoveries

Epigenomic studies from the Cho Lab have revealed significant insights into the epigenetic landscape of canine tumors. The identification of key DNA methylation patterns associated with specific tumor types and stages has led to a strong foundation for understanding the molecular basis of cancer in dogs. Moreover, the similarities between the epigenetic profiles of canine and human tumors highlight the relevance of comparative oncology studies using dogs and holds immense promise for translational applications. For example, the team has discovered that canine mammary gland tumors exhibit similar molecular subtypes and genomic alterations to breast cancers in humans. This allows researchers to harness existing knowledge from human breast cancer studies to successfully guide the diagnosis and treatment of canine mammary gland tumors. Similarly, the studies on canine osteosarcoma organoids have shed light on genomic drivers of the disease and have revealed potential therapeutic targets that may benefit both canine and pediatric patients.

Conclusion

Comparative medicine, particularly the use of canine-derived organoids, is a promising approach to advance our understanding of cancer and drive translational research. The molecular similarities between canine and human tumors, coupled with the availability of large-scale genomic data, mean that canine organoids are an invaluable resource. The mapping of the epigenome of the domesticated dog, and subsequent generation of canine organoids, has opened new avenues for studying cancer biology. By harnessing and analyzing these unique models, researchers can investigate the complex biological mechanisms of cancer development and treatment response, benefiting veterinary and human medicine by identifying novel therapeutic targets and developing personalized treatment strategies for both species. These successes underscore the reliability and relevance of comparative oncology research. As the field continues to evolve, collaborative efforts between veterinary and human oncology researchers are crucial for unlocking the potential of comparative medicine and improving outcomes for cancer patients of all species.

About the author:

Borris D. Aldonza is the facility manager of the Cho Lab within the Veterinary College of Medicine at Seoul National University. He is a PhD candidate in biomedical sciences, currently conducting research under the supervision of Professor Je-Yoel Cho. His investigations explore the systemic interactions of cancer cells within tumors, their microenvironment and distant organs, and how these interactions influence tumor pathobiology and treatment response. Aldonza actively contributes to the scientific community as a reviewer for renowned journals and maintains memberships in professional organizations.

References

1.  Son KH, Aldonza MBD, Nam AR, et al. Integrative mapping of the dog epigenome: Reference annotation for comparative intertissue and cross-species studies. Sci Adv. 2023;9(27):eade3399. doi: 10.1126/sciadv.ade3399