Tumors are more than an accumulation of malignant transformed cells. The presence of transformed cells triggers a response in the host organ, recruiting untransformed stromal cells like fibroblasts, immune cells, and endothelial cells that can either restrain and promote the growth of transformed cells. The ecosystem that is formed by a variety of different cell types, both transformed and untransformed, in conjunction with secreted components like extracellular matrix and signaling factors is called tumor microenvironment (TME).
Studying the TME is notoriously difficult. In pancreatic cancer, the tumor stroma comprises up to 90% of the tumor volume, indicating the importance of understanding how different cell types are working together in the TME. Communication between cell types has been traditionally studied using co-culture systems with two different lineages. However, this stark simplification of the multitude of signals in a native TME cannot replicate phenotypes observed in vivo. In vivo models offer the opportunity to study one naturally formed tumor per animal, thus making upscaling by testing multiple conditions under comparable conditions very costly, slow and laborious.
In this paper, we tackled the issue on how to study the pancreatic TME with all of its cellular and acellular components in a medium-throughput culture system. Based on pancreatic cancer samples isolated from tumor-bearing animals or surgically obtained patient-derived specimen, we developed an ex vivo culture system that allows for testing multiple drugs in the same intact TME and its maintenance for up to 7 days. Subsequent to incremental optimization of the culture medium, we characterized the TME by immunohistological stainings for a variety of untransformed cells, malignant cells and their proliferative capacity over time. Satisfied with our capability to keep the TME intact, we exemplified how our new explant culture system supports the elucidation of complex communication of various cell types via different signaling cascades.
In summary, we were able to trace a signaling cascade originating from malignant transformed cells to fibroblasts and endothelial cells, replicating a phenotype observed in vivo whose elucidation had escaped us for almost a decade. Thus, we introduced a new experimental tool that allows for studying complex phenotypes in system that can be influenced by recombinant proteins, depleting antibodies, drugs, and chemotherapeutic agents.
