Pancreatic Ductal Adenocarcinoma (PDAC), a highly aggressive form of pancreatic cancer, is known for displaying early metastasis and enhanced resistance against classical chemotherapeutic treatment regiments, leading to a very low overall survival rate. This troubling and detrimental pathophysiological feature, impeding and exacerbating patient’s treatment, is mainly caused by the characteristic fibrotic desmoplasia of the tumor microenvironment (TME), which mainly consists of so-called cancer-associated fibroblasts (CAF), extensive amounts of extracellular matrix and various other recruited types of tumor‑promoting cells.
In our research project, we established a 3D spheroid co-culture model using PDAC tumor cells and patient-derived cancer-associated fibroblasts to investigate the biological interactions and to analyse the efficacy and impact of novel drug candidates. A potential and promising therapeutical target is the significant cellular process of epithelial-mesenchymal transition (EMT), in which immobile tumor cells acquire migratory properties associated with increased malignancy, invasiveness and metastasis activity. The reversion of malignant tumor cells to their epithelial state is theorized to diminish chemoresistance and metastasis significantly, thereby improving the chemotherapeutic intervention and treatment. Further research includes an extension of our 3D spheroid co-culture model to include endothelial and immune cells, and a 3D tumor microenvironment-on-chip model for personalized drug testing.
As the largest organ of the body, the skin is permanently exposed to environmental hazards, radiation, chemical substances and biological agents, thereby forming the first line of immunological defense in the body. However, these factors can lead to serious skin reactions such as skin irritation, inflammation, allergies or cancer. Hence, there is a substantial need to screen and assess the toxicity of agents and the identification of efficacious novel drug candidates for the skin.
We are currently developing a novel human 3D immune competent full-thickness skin model according to the 3R principles (“replace”, “reduce” and “refine”), for pharmacological and toxicological compound assessment. For this, langerhans cell surrogates are integrated as central initiators of the immune reaction in the skin, implementing skin sensitization and inflammation in the 3D model. To assess the tested compounds, inflammatory pathways are investigated via sequencing and transcriptomic analysis and threshold values will be determined for putative compound classifications and perspectively for high throughput screenings.
Further research includes the integration of additional cell types e.g. melanocytes, melanoma cells or vascularization, allowing distinct disease modelling for drug discovery.
Conclusion: Phenanthroindolizidine alkaloids (PAs) show a broad range of bioactivity and hitherto blockade of inflammation was reported in cancer. However, the mode of action in Triple Negative Breast Cancer (TNBC) is unknown. Thus, we examined six natural derivatives and observed initial structure activity relationship with O-methyltylophorinidine as the most potent compound. We observed dose-dependent anti-proliferation, anti-inflammation and anti-tumor activity. The compounds maintain bioactivity under hypoxia and in microtumors with blocking microtumor growth and invasion. Nevertheless, PAs exhibit superior drug potential when compared to the standard of care agent Paclitaxel (data not shown). In conclusion, PAs may be investigated as a novel drug to treat inlfammation and hypoxia driven cancer, including TNBC.