Unravelling the Potential of Organoids in Cancer Research: Challenges and Solutions
Joseph Boyd, PhD., and Vi Chu, Ph.D., Cell Biology R&D, Life Science Business of Merck.
Organoids—complex, multicellular, 3-dimensional in vitro cell models used in biomedical research that closely mimic in vivo organs—are a powerful way to study drug responses, disease progression and more. These complex mini organs are helping to revolutionise our understanding of cancer, paving the way for personalised treatments and unlocking findings that traditional 2D cell culture models can’t reveal.
Scientists can grow patient-derived organoids (PDOs) from both healthy and tumour tissue biopsies. Recently, researchers have been using tumour PDOs as in vitro predictors to anticipate how patients will respond to chemotherapy. This demonstrates the importance of these models in identifying new anti-cancer treatments through drug screening.
Organoids are a powerful tool for studying development, disease and personalised medicine. However, this journey isn’t without its challenges as growing and maintaining these complex structures requires constant adjustments and optimisation. Researchers are rising to the challenge, developing innovative techniques to overcome hurdles like the lack of standardisation, limited maturation, scale up and phenotypic size and shape variability. Each breakthrough brings us closer to unlocking the full power of organoids.
The Power of Organoids in Medical Research
Organoids can be derived from various sources, including adult tissue, PDOs, and pluripotent stem cells (human ES/iPSCs). Isolation and expansion of the LGR5+ stem cell population are crucial for maintaining the organoids' self-renewal ability. Hans Clevers, the pioneer of organoid biology at the Hubrecht Institute, first demonstrated in 2009 that a single LGR5+ expressing intestinal stem cell could self-organise into crypt-villus structures like the adult intestine.
Since then, researchers have since succeeded in deriving organoids from a vast array of tissues, including the brain, colon, kidney, liver, pancreas, lung, and even tumour biopsies. Unlike flat cell cultures, these structures closely replicate these organs’ biological, structural and functional complexity. This makes organoids invaluable for studying drug responses, shedding light on disease progression and paving the way for personalised medicine. One of the advantages organoids afford for medical research is the ability to predict drug side effects and toxicity prior to transitioning a study involving expensive animal models, providing a lower-cost and more effective screening strategy for drug candidates.
For example, epithelial intestinal organoids, often referred to as enteroids or mini-guts, maintain the physiological characteristics of the gastrointestinal system and have been a helpful cell culture tool to model intestinal development and disease, including the study of colon cancer, celiac disease, inflammatory bowel diseases and host microbiome interactions. Biobanks of organoids derived from both normal and diseased tissues empower insights into variation of drug efficacy, toxicity, and side effects that are potentially masked by single-source-derived models.
Other critical and essential factors in maintaining organoids in culture include using lot-qualified growth-factor-reduced (GFR) Matrigel, following proper passaging techniques and sourcing high-quality organoid media and cell culture reagents. Although the learning curve for culturing organoids is higher than for traditional 2D cell culture, the potential for breakthroughs and enhanced insights that organoids reveal make the investment worthwhile.
Organoids in Cancer Research
Cancer research takes centre stage with organoids. Researchers have demonstrated that tumour organoids (tumoroids) maintain the key genetic and phenotypic features of their source tissue and tumour subtype, while also capturing the inherent diversity within the tumour.
Recently, tumour PDOs have been used as an in vitro predictor of chemotherapeutic treatment response, demonstrating the importance of these models in identifying new anti-cancer treatments through drug screening. A recently published study utilised pancreatic cancer organoids to identify an inhibitor to the Kras oncogene. In another study, a suite of patient-derived lung cancer organoids showed comparable chemotherapeutic efficacy to patient-derived xenograft animal models. Preclinical testing of tumour organoids from colorectal cancer patients has been shown to correlate with high predictive value for treatment outcomes. Using tumour PDOs helps guide the search for new treatments and tailors therapy for each patient’s unique blueprint.