Cancer Models Forum

Posted by Anna, October 2019

How organoids could bridge the gap between in vivo and in vitro preclinical cancer models

Organoids consist of 3D cultures of heterogenous cells which self-organise and function in a similar way to an organ. While they are surfacing as an innovative new technology for preclinical cancer research, they are still unfamiliar territory for most pharma and biotech researchers.

A hot question amongst the translational oncology community is what benefits does organoid technology offer over traditional preclinical cancer models? It is well-known that in vivo models suffer drawbacks of high expense and laboriousness, and, while, in vitro models may offer quick results, they are less comparable to tumours in vivo. But can organoids be thought of as a way to bridge the gap between these two approaches?

In our previous blog post in this series on organoids, we mentioned some of the exciting applications of organoids for preclinical cancer research. In this blog post, we’ll give you an overview of the advantages that organoid models can provide compared to traditional preclinical models.

Organoids vs in vitro cancer models

It is well established that although 2D cell cultures are cheaply and easily generated, they do not model cancer cells accurately due to their distorted morphology, genetic differences and lack of signalling cues (such as cell-matrix interactions.) However, this does make them a great starting point for preliminary research such as initial efficacy studies, or high-throughput screening of a library to find initial hits, before taking therapies into in vivo models. But what if researchers could use a more physiologically representative model during these early phases of drug discovery? Due to the fact that they are 3D cultures, organoids show more realistic cell morphology, experience complex signalling cues, and can be grown from tumour cells with little genetic drift.

Many studies have shown that organoids show greater differences in drug sensitivities than traditional in vitro models. Since many hits identified by screening with cell lines are later found to be ineffective or toxic in vivo, replacing cell lines with organoids could allow biopharma researchers to “fail fast, fail cheap”. This is due to the cost and resource saving benefits of discarding a bad candidate earlier.

Organoids vs in vivo cancer models

For preclinical experiments, in vivo models offer a more physiologically representative approach, but unfortunately these can be costly and can take months to develop if the right model doesn’t already exist. This is where organoids could come in, offering a cheaper alternative that can be generated in just a few weeks. The additional advantages over animal models include fewer ethical concerns and no species differences to account for.

But what about more specialised cancer models, such as for immuno-oncology studies, which typically require the use syngeneic mice models? Genetic engineering, immuno-oncology studies and growing of patient-derived tumours have all been shown to be possible using organoids. Investigation of toxicity over longer periods of time could also been carried out using organoids in a more cost-effective manner than in vivo models. In addition to this, they may be able to go a step further than some in vivo models - studies have shown promise in mimicking parts of the tumour microenvironment, such as the hypoxic core and blood vessels.

Current limitations of organoids

So, what are the drawbacks of using organoids as cancer models? The main problem is the lack of standardisation when it comes to protocols for organoid preparation and the media conditions used. Despite the fact that varying these parameters affects organoid growth and their characteristics, these differences have not previously been investigated in detail, leaving researchers concerned about the reproducibility of their data. However, the emergence of more commercial suppliers of organoids that have standardised preparation methods are helping to overcome this.

Another challenge surrounding the adoption of organoids into drug development is imaging. Their heterogenous shapes and mutational patterns make characterising the effect of a drug on organoid shrinkage hard to determine by eye. However, this problem could be solved by future advances in imaging techniques, such as artificial intelligence imaging. This technology also shows promise in being used to predict the metastatic potential of an organoid by analysing complex patterns in their shape which cannot be detected by the human eye.

Finally, in order to fully understand the developmental cues to supply when growing different organoids, further research is currently needed. This has been evidenced by some cases where organoids have not reached their full maturation, or sections have been found growing in the wrong area, which could affect their interaction with a therapeutic molecule.

That being said, there are many exciting studies which show the potential of organoids as effective cancer models, most notably for high-throughput screening and genetic engineering using CRISPR-Cas 9. As a result, were looking forward to seeing organoids hopefully becoming more commonplace in drug development in the future, complementing existing in vitro and in vivo models to accelerate cancer research.

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Image credit: © Science photo -