Tipping the balance Cell death deregulation in colorectal cancer

This thesis explores the role of BCL-2 family regulated cell death in colorectal cancer (CRC), with a detailed introduction to the topic in Chapter 1. In Chapter 2, we establish and characterize models to assess anti-apoptotic dependencies in intestinal stem cells. In Chapter 3, we employ these methods to elucidate BCL-2 family protein reliance in organoid models that reflect the progression pathway of CRC. Thereby, we establish BCL-XL to be crucial for CRC progression, which presents a key vulnerability of the disease and therefore also a valuable therapeutic target. Based on these findings, in Chapter 4, we performed a high throughput drug screen, which identified kinase targets that synergize with BCL-XL inhibition to target colon cancer stem cells. More importantly, we elucidate a novel resistance mechanism that is rapidly activated upon BH3 mimetic treatment and is mediated by FGFR4 signaling induced MCL-1 expression. In Chapter 5, we evaluate BCL-2 family dependencies in a panel of CRC cell lines, thereby assessing molecular features that could predict sensitivity to specific BH3 mimetics. Lastly, in Chapter 6, we integrate the findings outlined in this thesis and discuss their implications for our understanding of cell death regulation in CRC development, progression and therapy response.