The role of cell competition in intestinal cancer: from primary tumor to liver metastasis

The significance of cell competition in disease, particularly in cancer progression, has become increasingly apparent. Throughout tumorigenesis, cell-to-cell interactions play a key role in enabling cells to assess the fitness of their neighboring cells. This leads to the establishment of whether mutated cells will be outcompeted by healthy tissue, employing competition as a tumor suppression mechanism. Conversely, aberrant cells may become “supercompetitors,” and win the battle with healthy cells. In this thesis, we delve into the interactions between intestinal wild-type and cancer cells during primary tumor and metastasis formation. Chapter 2 outlines the development of a co-culture system that enables the investigation of direct cellular interactions between two epithelial cell types within the same organoid. This model allows the dissection of interactions between cells with a differential fitness based on both direct contact and short-range paracrine signaling. Our focus lies specifically on the interaction between intestinal wild-type and cancer cells, and it excludes the influence of non-epithelial cells such as those of the immune system. In Chapter 3, we demonstrate that the presence of intestinal cancer cells induces wild-type intestinal cells to revert to a fetal-like state. This reversion is accompanied by increased JNK activation and results in the active elimination of the wild-type population. Cancer cells exploit this competition to enhance their own growth. Chapter 4 explores cell competition in a metastatic environment. We observe that intestinal cancer cells cause compaction of liver progenitor cells, leading to forced differentiation that is characterized by a cell-cycle arrest. While active elimination of liver progenitors is not observed, cancer cells can exploit these competitive interactions to increase their proliferation. In microtissues, competitive behavior of cancer cells manifests differently, here wild-type hepatocyte-like cells are used as a growth scaffold by cancer cells and subsequently actively eliminated. In Chapter 5, we investigate the dual role of the JNK pathway in cell competition in liver metastasis. We find that JNK activation is reduced in liver progenitors during competition, suggesting a pro-proliferative role that supports the maintenance of a progenitor state. However, JNK activation is increased in wild-type hepatocytes near cancer cells, indicating activation of this pathway during outcompetition of these differentiated cells. Additionally, we explore the role of YAP/TAZ in cell competition, observing a significant reduction in YAP activation in competing liver progenitors. Enhanced activation of YAP is sufficient to protect liver progenitors against outcompetition by intestinal cancer cells. Lastly, Chapter 6 demonstrates that the in vivo liver microenvironment, promotes the colonization potential of intestinal cancer cells. This suggests that competition between cancer and liver cells induces adaptation of cancer cells to the liver environment, enhancing their ability to disseminate and colonize this tissue.