An increasingly appreciated concept in the study of adult organs is the ability of resident stem cells to not only replenish healthy tissues, but also repair them after injury. Tissue repair stem cells must rapidly act to repair a tissue, which poses a risk, as misregulated use of such stem cells can lead tissues to acquire cancerous properties. A current challenge is to understand how tissue stem cells balance the need for an appropriate tissue injury response while avoiding transition to a cancer-like state. New evidence suggests the genetically tractable Drosophila provides a rapid model to study these same processes with single cell resolution. We propose to use the Drosophila hindgut (large intestine) to find connections between a stem cell response to injury (infection) and acquisition of a cancer-like property (dissemination from the epithelium). Injury by chronic infection plays a major role in intestinal cancers, but mechanisms by which infection promotes carcinogenesis are poorly understood. Modeling these complex processes is now possible in Drosophila infected with the human opportunistic bacteria Pseudomonas. Infection significantly promotes dissemination of oncogenic Ras mutant cells. These hindgut cells exhibit several hallmarks of metastasis: separation from the primary tumor, invasion through the basement membrane, and subsequent migration to distant site. While the hindgut was the only organ found to possess disseminating cells following infection, the origin of the dissemination-prone cells has yet to be studied. Our preliminary data suggest that a small subset of Wnt-positive hindgut repair stem cells that respond to tissue injury is the primary origin of disseminating cells. Our central hypothesis is that such stem cells are uniquely predisposed to dissemination. The fact that Drosophila hindgut cells are capable of infection-induced cell dissemination, coupled with our expert knowledge of hindgut cell biology and the use genetic tools to examine single cells, places us in a unique position to elucidate how tissue injury by oncogenic stress and infection can lead to the development of metastasis. To goal of this proposal is to precisely map the origin of disseminated cells and elucidate the molecular circuitry of injury-induced cell dissemination.
Following tissue injury, many tissues use stem cells for tissue repair. During repair, the stem cell response must be carefully regulated to avoid a transition to a cancerous state. We propose to use the Drosophila hindgut (large intestine) to find connections between a stem cell response to injury (infection) and acquisition of a cancer-like property (dissemination from the epithelium). The goal of this proposal is to both precisely map the origin of disseminated cells and to elucidate the molecular circuitry of injury-induced cell dissemination.
| Sawyer, Jessica K; Cohen, Erez; Fox, Donald T (2017) Interorgan regulation of Drosophila intestinal stem cell proliferation by a hybrid organ boundary zone. Development 144:4091-4102 |
