Importance of Realistic Tumoroid Models in Cancer Drug Screening
Tumoroids (“tumor-like organoids”) are valuable tools in personalized medicine.
They are being refined to include vascularization to study the role of angiogenesis in cancer development and drug targeting and address the problems of failure in anti-cancer drug screens and resistance to treatment.Tumoroids: valuable tools in cancer research and translational medicine
The fight against cancer is aided by model systems supporting basic research into tumor biology and the tumor microenvironment (TME), cancer drug development, translational research, and personalized medicine, including functional drug screening. Achieving this has involved a shift from 2D to 3D cell cultures to increase the dimensionality of cell-cell interactions, providing a phenotype that can recapitulate in vivo biology but can be performed in vitro (1).
Tumoroids are now regarded as being comparable to laborious patient-derived xenograft (PDX) models and the in vivo environment (2). Tumoroids are essentially “tumor-like organoids” that are typically prepared using cells from primary tumors harvested from patients and can therefore mimic the microenvironment of a specific tumor. They are a better predictive drug discovery tool than 2D models, and they show promise in guiding personalized medicine, including immunotherapy (3, 4, 5).
A key role in personalized medicine and drug screening
Tumoroids prepared from the tumors of individual patients are valuable tools in cancer research. They also have great potential in personalized medicine, for example, drug screens to identify effective drugs against individual tumors. Patient-derived tumoroids (PDT) have two major advantages:
1. They retain key characteristics of the original tumor, including morphology, genomic profiles, and mutations, thus recapitulating the genetic and phenotypic heterogeneity.
2. The PDT approach enables the rapid generation of an informative model system, which is critical when screening drugs for individual patients (days or weeks compared to months for PDX).
One example of the value of tumoroids in personalized medicine is a study on lung cancer (6), a cancer form that shows substantial genetic and phenotypic heterogeneity across individuals, making it a particularly interesting target for personalized medicine. Tumoroids and normal bronchial organoids were readily established from patient tissues and recapitulated the original tissue architecture and genomic alterations. The tumoroids could then be used to predict patient-specific drug responses.
Refining the tumor model
Mimicking the natural TME requires more than 3D models based on cancer cell lines. The TME comprises extracellular matrix (ECM), stromal cells, and lymphatic vascular networks. Different tumor types may require special approaches, as exemplified below.
Establishing an air-liquid interface
When establishing lung tissue and tumor models, generally it requires the air-liquid interface (ALI) to promote the differentiation of airway epithelial cells. Tumoroids cultured at the ALI can, for example, be used in the study of aerosol-based drug delivery (7). Lung organoids generated on permeable membranes that provide an ALI are also valuable in research on respiratory toxicants and pathogens, including SARS-CoV-2 causing COVID-19 (8, 9).
Incorporating vascularization to research and target angiogenesis
Poor drug transport and delivery, which can depend on both the microvessel network of the TME and the vascularization around the tumor, are major causes of failure in anti-cancer drug screens and resistance to treatment. Not only that, the process of angiogenesis during tumor progression is itself a target for drug development (10), and the effects of drugs or genetic manipulations on sprouting angiogenesis can be measured using the spheroid-based sprouting assay (11,12, 13). Including vascularization within and around the PDT is therefore essential to accurately recapitulate in vivo conditions.
In the second article in this series, we will look at an example of how vascularization can be incorporated into a PDT model to ensure that the TME and its surroundings are replicated as quickly and accurately as possible for functional drug screening.
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References
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