Using 3D cell cultures to fight anti-cancer therapy resistance

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Example of an in vitro culture of mammary tumor organoids. The green cells under

Example of an in vitro culture of mammary tumor organoids. The green cells under the fluorescent microscope (right side) are genetically modified to study mechanisms of anti-cancer therapy resistance. University of Bern

An international research team headed by the University of Bern and the Netherlands Cancer Institute has developed 3D cell cultures in which genes can be specifically modified. They allow the study of genes that may cause therapy resistance in breast cancer. This knowledge may further improve the use of targeted anti-cancer drugs.

Drug resistance remains the major cause of death of patients suffering from metastasized cancer. Unfortunately, there is no ideal therapy that suits all patients. Moreover, the most efficient therapy should be used right from the start to increase the chance of cure and to minimize the risk of drug resistance. Therefore, an important goal in modern cancer research is the development of individualized therapies for cancer patients, the so-called precision medicine. In close collaboration with the Netherlands Cancer Institute (NKI) in Amsterdam and the Hubrecht Institute in Utrecht, a research team at the University of Bern has generated 3D cell cultures (so-called organoids) to investigate mechanisms of drug resistance in breast cancer and to improve current therapy. The corresponding article was just published in "Nature Methods".

Targeted analyses using molecular scissors

How to identify the best therapy for an individual patient? "We are studying whether so-called organoids are useful to elucidate mechanisms of therapy resistance and to predict therapy response," says Sven Rottenberg from the Vetsuisse faculty of the University of Bern. For this purpose, the scientists are culturing the tumor cells in a three-dimensional matrix and complement the culture medium with special growth factors. Using the molecular scissors CRISPR/Cas9, specific genes in these 3D cell cultures can be modified to investigate the effect on therapy response. This approach may be useful to mimic therapy response of patients and to find the optimal therapy in vitro.

A possible alternative to animal experiments

In contrast to classical cell cultures, organoids have major advantages, explains Sven Rottenberg: "This method opens new possibilities, since 3D organoids grow much more efficiently in the Petri dish - and they keep special features as well, including the typical cellular heterogeneity of cancer." This is unlike the few selected tumor cells that grow under conventional cell culture conditions and often do not represent the original tumor anymore. The hope is that this approach replaces the cumbersome transplantation of human tumor fragments into mice. "This would reduce the number of complex animal experiments," adds Rottenberg. Nevertheless, he also sees work ahead: "Regarding therapy response we see in our model that not all organoids tested in vitro predict the real in vivo response correctly. For some tumors, we are still missing factors that influence drug response and that cannot be modelled sufficiently with the current organoid approach." The research group of Sven Rottenberg is working on further optimizing the cell culture conditions to put the puzzle of drug resistance mechanisms together.

Support from the European Framework Programme Horizon 2020

Sven Rottenberg has been working at the University of Bern since August 2014, closely together with the Netherlands Cancer Institute in Amsterdam. His research is supported by the Swiss National Science Foundation (SNF) and the Dutch Cancer League (KWF). In the past year, Rottenberg received support from the European Research Council (ERC) for researching cancer therapy resistance. The ERC supports excellent research in the framework of the Horizon 2020 programme.

Publication details

Duarte AA, Gogola E, Sachs N, Barazas M, Annunziato S, de Ruiter JR, Velds A, Blatter S, Houthuijzen JM, van de Ven M, Clevers H, Borst P, Jonkers J, Rottenberg S (2017). BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance. Nature Methods, in press. Doi: 10.1038/nmeth.4535

Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, Balgobind AV, Wind K, Gracanin A, Begthel H, Korving J, van Boxtel R, Duarte AA, Lelieveld D, van Hoeck A, Ernst RF, Blokzijl F, Nijman IJ, Hoogstraat M, van de Ven M, Egan DA, Zinzalla V, Moll J, Boj SF, Voest EE, Wessels L, van Diest PJ, Rottenberg S, Vries RGJ, Cuppen E, Clevers H. A living biobank of breast cancer organoids captures disease heterogeneity. Cell, in press. Doi: 10.1016/j.cell.2017.11.010