Location, location, location: an imaging approach to identify homeostatic cell elimination mechanisms in the adult pancreas.

Epithelial tissues line our inner organs and act as protective barriers to the external environment.

Cells are the building blocks of our tissues and in an epithelium, cells tightly connect to each other to form the impenetrable barrier. Epithelial cells also use cell-cell connections to communicate and monitor each other.

This ensures that dying cells are removed and replaced with new cells at the appropriate time, and in a controlled manner. Any deviation from this process would result in a leaky barrier and would increase the risk of disease.

As we age, our cells often acquire genetic mutations, some of which are harmful because they reduce the ability of a cell to work properly and respond to cues from the tissue. How do tissues respond to the presence of genetically mutant cells?

To address this question, we use innovative experimental systems that allow us to randomly switch on a genetic mutation in a minority of epithelial cells in an otherwise healthy tissue.

We label genetically mutant cells with a fluorescent tag so we can follow where mutant cells are in the tissue over time using microscopy.

We focus on adult pancreas tissues because the genetic mutation expressed in cells is directly linked to pancreatic cancer and we currently know very little about how pancreas tissues stay healthy in adulthood.

We discovered that adult pancreas tissues expel the genetically mutant cells and proper cell-cell connections with normal cells are essential for this to occur.

Our research also revealed that some genetically mutant cells are never eliminated and instead remain in the tissue, where they slowly develop into the early stages of cancer.

We recently recorded what genes are expressed in genetically mutant cells that are never eliminated and found that these cells switch on genes that control cell survival, tissue injury responses and stem cells.

These data suggest that 'never eliminated' cells take on the characteristics of an injured or stem-like cell to avoid being eliminated.

However, research shows that every epithelial cell in the pancreas has the potential to become a stem cell to repair a damaged or injured tissue. This raises the question as to what controls why some of the mutant cells are retained while others are eliminated.

In this project, we will test the possibility that cell elimination outcomes (that is whether a genetically mutant cell is eliminated or not) are predictable and depend on where a mutant cell sits in the tissue.

We will use new technologies to image genetically mutant cells in pancreas tissues before and after cell elimination has occurred and simultaneously measure changes in genes expressed in both mutant and normal cells.

This will allow us to identify the communication signals between normal and mutant cells before and after cell elimination and determine whether the same signals operate across different parts of the tissue.

By taking this approach, we will also ask whether a mutant cell is using signals from the local tissue architecture to avoid being eliminated.

We will also experimentally test whether switching to a become more like a stem cell allows mutant cells to avoid cell elimination signals and remain in tissues.

An improved understanding of the mechanisms controlling tissue health will lay the foundation for future studies to assess how these mechanisms decline with age and in disease.