Feasibility of Patient-Derived 3D Gastrointestinal Stromal Tumour Models as Alternatives for In Vivo Mouse Models

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and a key example for targeted therapy with tyrosine kinase inhibitors (TKIs), which have significantly improved survival rates. However, no effective treatments exist for TKI-resistant or mutation-negative tumours. Until now, research on the effects of TKIs has mainly used 2D cultures or mouse models, lacking patient-specific 3D GIST models. We investigated various 3D GIST models, including spheroids, organoids, patient-derived microtumours (PDMs), and precision-cut tumour slices (PCTSs), to assess their feasibility as alternatives for 2D cell culture or in vivo mouse models. Moreover, 2D monolayer and 3D spheroid GIST cell lines showed mutation-dependent responses to TKI treatment, but differences between 2D and 3D cultures were minimal. Thus, patient-derived 3D models, incorporating tumour microenvironment cells, were developed for more accurate in vivo representation. PDMs and PCTSs were successfully isolated from primary tumours and cultivated for up to two weeks. Three-dimensional models were immunohistochemically characterised, and the response to TKI therapies was tested and compared with expected clinical outcomes. In addition to already established 2D cell cultures and mouse models, PDMs and PCTSs are novel patient-derived 3D models that can be used to study tumour cell interactions within the microenvironment. Moreover, they could be used to investigate TKI resistance, and novel treatment options such as immunotherapies and combination therapies.