Despite the advances in our understanding of cancer pathology, remarkably little is known about its earliest stages of development, when a cell harboring a pro-oncogenic mutation overtakes surrounding healthy tissue and grows into a preneoplastic field. Sequencing analysis suggests cells in these fields typically exhibit altered expression of one or more oncogenes and/or tumor suppressors and, in many cases, descend from a single proliferative cell. Although the mechanisms allowing this rogue cell to expand into a centimeters wide field at the expense of healthy tissue remain unclear, it bears striking similarity to the dynamic process of cell competition. Cell competition is a highly conserved developmental process describes the ability of cells in a tissue field to sense each other?s relative fitness and actively eliminate less fit, but otherwise viable cells from the field. A variant of the process, identified while studying the proto-oncogene Myc, has a single profound difference. Here, when cells expressing elevated levels of Myc appear in a tissue field, it is the neighboring healthy cells that are actively eliminated, a process referred to as ?super-competition?. In this context, not only are healthy cells identified as less fit than their oncogenic neighbors, but their death spurs the proliferation of Myc expressing cells, enhancing their encroachment into the surrounding healthy tissue. The list of contexts known to induce super-competition now includes mutations deregulating the JAK/STAT, Wnt, and Hippo signaling pathways, all of which are identified as either oncogenes or tumor-suppressors in human cancers. Here, we propose to further study the molecular and genetic interactions underlying the death of healthy cells during cell competition, an event mediated by NF-kB signaling through a pathway co-opted from the innate immune response. We hypothesize NF-kB transcription factors activated during competition not only induce apoptosis of healthy cells, but also promote the release of locally acting growth factors, which results in the increased proliferation of Myc expressing cells. In this project we will determine whether this signaling module functions in other contexts of cell competition, identify the direct and indirect transcriptional targets of NF-kB during Myc induced cell competition, and develop a molecular biosensor of cell competition. We believe these experiments will allow us to uncover genetic and environmental factors that alter a tissue field?s susceptibility to preneoplastic field growth, thus identifying potential chemopreventative therapeutic targets.
Specific Aim 1 : Define the full extent of NF-kB activity in cell competition.
Specific Aim 2 : Identify the transcriptional program activated by NF-kB during Myc competition.
Specific Aim 3 : Construct a molecular biosensor of endogenous cell-competition.
The growth of preneoplastic fields, a critical first step on the path towards malignancy, bears striking resemblance to Myc induced super-competition, a highly conserved developmental process that results in the expansion of cells expressing elevated levels of the proto-oncogene Myc at the expense of nearby healthy cells. By studying Myc induced super-competition, we intend to uncover potential therapeutic targets that restrain the growth of preneoplastic fields, thus delaying the onset of incipient cancers and prolonging their remission.
