The role of cell competition in intestinal cancer: from primary tumor to liver metastasis
Authors:   , Krotenberg Garcia Ana 
Published: May 2024

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.