Crossing Borders: Manipulating stemness through carcinogenesis

Colorectal cancer (CRC) is one of the most common cancers worldwide. A strict balance of cell growth and cell death maintains intestinal homeostasis and when disrupted tumor formation is initiated. Intestinal homeostasis is maintained, by the so-called intestinal stem cells (ISCs). Similarly the so-called cancer stem cell (CSC) population has been held responsible for driving tumor growth and progression. Intriguingly, the CSCs have been found to be less sensitive to chemotherapeutics and drive tumor-resistance. Understanding the mechanisms behind these driving populations, in both normal and tumor homeostasis, could potentially lead to the development of new therapeutic tools and targeting strategies. Using 3D in vitro culture models we have developed techniques to study regulation and homeostasis throughout the different stages of CRC development in murine and human tissue. Interestingly, despite the increasing mutational status, a conserved functionality in major signaling cascades was observed in all stages of tumorigenesis. Interestingly, further work presented in this thesis suggests that despite relying heavily on the apoptotic pathway, specific apoptotic modulators could be held responsible for driving specific functions in stem cells. For example, BCL-2 was found to play an essential role in transformation, whereas BCL-XL was essential for CSC maintenance. Determining whether there is indeed an apoptotic switch could potentially reveal a potential therapeutic window. Furthermore, defining crosstalk between different signaling pathways could provide insights into potential resistance mechanisms. Herewith, the combination of healthy versus tumor organoid systems could potentially prove instrumental, helping bridge the gap between cancer genetics and patient trials