723B Poster - 11. Cell division and cell growth
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Pablo Sanchez Bosch; Bomsoo Cho; Jeffrey Axelrod

Affiliation: Stanford University

Keywords:
s. cell competition; h. tumorigenesis

Cell competition is a process by which cells with a competitive advantage (winners) eliminate less fit neighboring cells (losers). This phenomenon was first seen when cells harboring ribosomal protein mutations were eliminated by their WT neighbors. Since that first observation in 1975, cell competition has been linked to mutations in many other genes, i.e. tumor suppressors, oncogenes, or cell polarity components. Even though the outcome is always the elimination of the less fit cells, very little is still known about the mechanisms leading to the selection of fitter cells and elimination of the losers. Tumors have been seen taking advantage of cell competition to outcompete the surrounding WT tissue and promote survival and local invasion. Therefore, understanding the molecular cues of cell competition will give us not only insight into a key developmental process but a deeper understanding of tumorigenesis.

We have found that Fmi, a key component of the planar cell polarity (PCP) pathway, plays a critical role in various cell competition scenarios and Ras^V12-dependent tumorigenesis. Intercellular Fmi homodimers scaffold the assembly of the other core PCP proteins and mediate asymmetric signaling between the core PCP proteins. PCP signaling polarizes cells within the plane of the epithelium to orient cellular structures, cell divisions, and cell movement during development and homeostasis. In addition to establishing planar polarity, numerous reports have linked PCP signaling to cancer.

Our experiments show that Fmi is critical for winner cells in cell competition and tumorigenesis. Tumors and winner cells lacking Fmi lose their ability to eliminate neighboring loser cells. Moreover, fmi-null winners undergo apoptosis. Removing Fmi from loser cells does not have any effect on cell competition outcomes, suggesting that Fmi is only critical by winners to outcompete losers. Our findings suggest that Fmi acts as a scaffolding and signaling hub, where Fmi molecules, via PCP or other signaling networks, allow for efficient cell communication, necessary for the elimination of loser cells.

Our results are striking in that Fmi is critical in all the study cases we’ve tackled, and establish the necessary background for comprehending the mechanisms underlying cell-cell communication during both developmental cell competition and tumorigenesis.