Preclinical cancer models are vital for the efficient translation of basic cancer research into innovative treatment regimens for cancer patients. 2D culture models from immortalized cell lines are the fundamental tools for disease modeling and drug development as these models are easy to create and maintain. However, these models lack the physiological relevance and biological complexity that are commonly observed in 3D models. Moreover, improved targeted therapy in pre-clinical model systems are crucial for understanding the inter- and intra-tumour heterogeneity.
3D culture models such as organoids revolutionized the basic and translational research field over the past decade. Organoids are cultures of cells that proliferate as multicellular structures in semisolid matrices in the presence of mitogens and pathway modulators. Organoids exhibit gene and protein expression signatures closer to those observed in vivo. Organoids can be derived from embryonic and adult stem cells and exhibit self-organizing capacities and phenocopy essential aspects of the organs they are derived from. Organoid technology provides better opportunities to understand the complex cell biology in a physiologically relevant framework and shows greater potential in many applications including disease modeling, generating biobanks, regenerative medicines and therapeutics. Organoids can also be grown from patient-derived healthy and tumour tissues with high efficiency, which potentially enables patient-specific drug testing, development of personalized treatments, thereby opening up new avenues in precision medicine. Developing personalized anti-cancer therapy through drug screening, optimizing immunotherapy and identifying prognosis related hallmarks are critical in advanced cancer therapeutics.
Cancer organoids are a great model to study how tumours develop and how they respond to treatments. Recent studies show that organoids can be generated from various human cancers including liver, breast, pancreas, colon, bladder and prostate and these models are helping us expand our knowledge on the etiology and characteristics of these malignancies. Culturing organoids can be technically challenging, but once established they can provide greater insights into translational research.
The most important steps in generating 3D organoids are as follows,
Select the right cell line that best represents the biology that you are trying to replicate.
Select the right culture matrix in developing the best culture system as the cells need a kind of microscopic scaffold to stick to.
Morphology and molecular characterization of organoids with accurate cellular and biochemical makeup are paramount in establishing the 3D model.
Generation of patient-derived organoids from normal and cancer tissue (adapted from Kretzschmar, K., 2021).
At the CDH, we are focused on establishing a ‘living’ tumour organoid biobank from primary patient samples and are exploring the possibilities of using various tumour organoids as an alternative preclinical model for drug discovery, personalized anti-cancer therapy and immuno-oncology. ‘Living’ organoid biobank can be used for drug screening and studying inter and intra-tumour heterogeneity by analyzing gene expression profiles, proteomics and mutational signatures. Cancer organoids can be transplanted into mice to study tumour cell invasiveness and metastasis. Cancer organoids can also be co-cultured with non-neoplastic stromal cells or immune cells which help in discovering the tumour microenvironment. With all these efforts, it is possible in the future that cancer patients might have an organoid made from their tumour not for research, but to help with their treatment.
Applications of patient-derived organoids in cancer research (adapted from Kretzschmar, K., 2021).
Dr Nimmi Baby
Tumor Models Lead, Cancer Discovery Hub
National Cancer Centre Singapore
Comments