The unfolded protein response in intestinal stem cells: A focus on cancer

To date, colorectal cancer is highly responsible for cancer-related disease and mortality in Europe. Treatment options vary between surgery, irradiation- and chemotherapy. Fortunately, many advances have been made throughout the years to optimize and personalize treatment, aiming to reduce disease burden, comorbidity and mortality. Our studies focussed on epithelial stem cells of the intestine: with their self-renewal and production of epithelial progenitor cells, they play a key role in maintaining homeostasis or (preventing) disease development, such as cancer. Therefore, intestinal stem cells are an interesting and promising target for (future) therapies. Our intestinal stem cell studies evolved around an intrinsic cellular process regarding protein synthesis, termed the Unfolded Protein Response (UPR). In this thesis, we aimed to unravel the influence of this cell-autonomous pathway (UPR) on intestinal epithelial stem cell fate. We observed that manipulation of the UPR in intestinal epithelial stem cells, either pharmacologically or genetically, could be used to beneficially influence the process of carcinogenesis in the intestine in vitro and in vivo, without affecting normal, healthy, tissue. In a world in which therapies for colorectal cancer including personalized medicine and tumor-specificity are currently evolving, targeting a cell-autonomous pathway such as the UPR, could prove to be both effective and elegant