Tissue dynamics in homeostasis and cancers of the pancreas and gut

Recently it has been speculated that stem- and progenitor cells are not only important during development to generate different organs, but also in many adult tissues to maintain tissue homeostasis and recover from injury events. Importantly, also the growth of solid malignancies is thought to depend on cancer stem cells for expansion and relapse after therapy. Therefore, understanding the cellular dynamics during health and disease might lead to important insights to develop potential new therapies. In this thesis, we have employed proliferation-dependent, marker-agnostic lineage tracing systems in combination with quantitative models to provide insights in the fundamental characteristics of tissue homeostasis, repair and cancer growth, in two gastrointestinal organs; the intestine and the pancreas. In the adult pancreas we found that all acinar cells have an equal ability to contribute to pancreatic tissue homeostasis and regeneration after pancreatitis induction. In colorectal cancer and pancreatic ductal adenocarcinoma, we found that tumor expansion is driven by long-term clonogenic cells, mainly occurring in those regions that are rich in cancer associated fibroblasts. This implicates that cancer growth is defined by the tumor microenvironment, which is in stark contrast to the classical stem cell model which assumes cancer stem cell properties to be fully intrinsically defined. This has important implications for treatment development since it does not seem to be effective to only target a purported cancer stem cell population. Considering the important interplay of the microenvironment and the tumor cells, future research should also be focused on identifying responsible factors from the microenvironment that drive disease initiation and progression.