Harnessing next-generation cell culture methods in the fight against cancer

The dream of precision medicine, or personalized medicine, is moving ever closer in the world of cancer treatment. The desire to match individual patients with the best drug treatment administered at just the right time has long been the goal of precision medicine, but the advent of patient-derived 3D organoid cell cultures has brought that goal clearly within reach. Organoids derived from recently harvested tumors can now be expanded into organ-like structures to generate patient-specific cancer models in a matter of weeks.

Whereas most labs will focus on culturing an organoid for a very specific cancer type, there is an institute at Weill Cornell Medical College (WCMC) in the US that is taking a unique, platform-based approach to the technology. Dr. Laura Martin is the Ex Vivo Models Director at the Englander Institute for Precision Medicine (EIPM) at WCMC in New York. She is the custodian of a biobank of over 120 organoids comprising at least 11 different types of solid tumors. These are heady times for cancer drug discovery and the location of the EIPM on the premises of a major metropolitan hospital is driving its success.

3D organoid platforms

Conventional 3D cell culture is now used in many biological assays, especially those that rely on replicating a cell’s microenvironment. Whilst spheroids and organoids have become the principal 3D culture methods, Martin’s goal is to create organoid platforms that recapitulate the cellular and genetic diversity of the original tumor (any tumor), which can then be used to test drugs or combinations of drugs that could not possibly be tested in the patient. That is easier said than done, however, as Martin attests; “Sometimes you collect the sample [from the cancer patient] and the tumor is not pure, or you have some normal cells. Since the media conditions and growth factors are not optimized for every type of tumor, the normal tissue can overgrow the tumor cells.”

In other words, it is possible to start out with a tumor biopsy but end up with normal tissue that has to be discarded. Getting an organoid line through five passages provides a good indicator that the line is successfully established, but then a suite of checks including a tumor ratification assay and histopathology is needed. “Once we verify the identity of the organoid, then we can proceed to drug screening,” Martin says.

Establishing a functional organoid for one specific cancer type is challenging enough, but Martin is aiming to do this for almost any type of tumor that comes from patients in the hospital next door. “What makes this unique is we are in a hospital setting where we are in constant communication with the physicians. They see the patients and we are the research part,” she says.

The demands involved in recapitulating new tumor organoids are met through an international consortium called the Human Cancer Models Initiative, funded by the US National Cancer Institute and the Hubrecht Institute in the Netherlands. “For new types, it’s challenging. We go through the literature and we have a large collaborative effort trying to get expertise from different people that can help us optimize the growth conditions for different types of tumors,” Martin says.

And that is where the right extracellular matrix (ECM) comes in. Accurate recapitulation of a tumor’s microenvironment, such as the incorporation of fibroblast stroma cells, relies on ECM and for Martin there is only one option.

The matrix of choice

The EIPM uses Corning^® Matrigel^® matrix, and it was during her post-doctoral research that Martin first discovered its versatility; “I set up in testing organoids in the lab where I did my post-doc. I tested these different ECMs, and really the only thing that works best across different organoids is Matrigel matrix. Once you have 200 organoids growing in Matrigel matrix you are a bit hesitant to change.”

Martin points out that it is generally not beneficial to have some tumors growing in one matrix and some in another. It turns out that tumors are quite ‘particular’ and changing things around is not generally feasible in terms of achieving a good end result. And that is certainly the name of the game in cancer organoid models; “The aim of all this is to have a model that better represents the patient so you can test things to offer to them,” she asserts.

Future developments

Martin sees two areas in which future developments will advance organoid cancer cell models and their use in drug screening. The first is in the tumor’s microenvironment in culture. “We are all trying to move the organoid technology to the next level, trying to make them more specific, more accurate, representing the tumor morphology. We could have a more automated culture system, but right now we don’t have the space or capability to do it,” she says.

And the second is at the drug testing end of things, for which she adds: “The platform that we are developing is a high-throughput drug screening robotic platform that will automate the drug screening.”

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