Professor of Cell and Developmental Biology*
*And Affiliate, Division of Genetics and Development
Epithelial Architecture: Polarity, Tumor Suppression, and Morphogenesis
Research in my laboratory focuses on the biology of epithelia, the fundamental tissue of all animals and the major constituent of human organs. We study the molecules and mechanisms that govern epithelial polarity, cell shape, and tissue morphogenesis, often using forward genetic screens in Drosophila as entry points. We also seek to understand how epithelial organization promotes the proper control of organ growth, a surprising connection uncovered by our analysis of fly tumor suppressor genes that represents a general principle relevant to human cancer. Finally, we use Drosophila cancer models as a simple system to understand how tumors actually kill their hosts.
How is the polarity of epithelial cells established and maintained?
Epithelial cells constitute the most widespread and evolutionarily ancient mode of animal tissue organization. The functions of epithelia rely on their highly polarized architecture, in which specific proteins are restricted to apical, junctional, and basolateral surfaces. We are working to understand the mechanisms that regulate cell polarity, exploiting our discovery of the Scribble module that acts to distinguish the epithelial basolateral domain by antagonizing the apical Par/aPKC complex. Cell biological assays of protein trafficking and biochemical studies of Scribble module partners are revealing their mysterious basic polarizing activities. As novel insights can come from unbiased genetic screens, we have designed several to isolate new regulators of epithelial polarity. These screens identify genes that directly interface with the conserved polarity regulators, revealing mechanistic links with basic membrane trafficking, RNA localization, and protein degradation machineries. Through this, we seek to expand existing paradigms of epithelial polarity and obtain an integrated picture of how the cell achieves the proper apicobasal distribution of proteins.
How does epithelial polarity influence tumorigenesis, and how do tumors kill their hosts?
The final size of animal organs is tightly regulated. How epithelial cells communicate to measure organ size, and to make a communal decision to cease proliferation, is an outstanding mystery. We are exploring the unknown pathways that control organ size, and in particular how the unique features of epithelial architecture restrain excess growth. Cell polarity and proliferation appear coupled in a number of contexts, and disruption of epithelial polarity correlates with the progression of malignant tumors, but the causal mechanism has been obscure. In Drosophila, mutations in Scribble-like polarity regulators induce fly ‘neoplastic tumors’ that share characteristics with malignant human tumors, including an inability to exit the cell cycle, failure to differentiate, loss of epithelial structure, and the acquisition of invasive capabilities echoing metastasis. We are currently using this system to address questions including: Why does control of organ size require epithelial organization? What factors lie downstream of neoplastic tumor suppressors to prevent malignancy, and what are the signaling pathways through which these factors are controlled? How do the pathways misregulated in tumorous growth relate to those that normally control wound healing and regeneration? Finally, we have found that fly tumors also induce tumor-host interactions resembling those seen in human patients, including cachexia and early death --can the fly model shed light on mechanisms by which tumors actually kill? These questions are being pursued through both hypothesis-based and discovery-driven approaches.
What molecules and forces control the shape, organization, and movement of epithelial tissues?
In addition to static aspects of epithelial architecture, we are interested in how epithelial cells and sheets organize themselves to drive the morphogenetic outcomes that shape organs and organisms. The ovarian (follicle) epithelium of Drosophila is a rich system for such studies, whose conserved morphogenetic behaviors determine the final three-dimensional form of the mature egg. We are using cell biological, live imaging, and biomechanical approaches in conjunction with forward genetic screening to understand the morphogenetic processes that sculpt this simple organ. One current focus is the mechanisms underlying tissue elongation, an elemental morphogenetic change that requires activities in both the epithelium and the surrounding extracellular matrix. These activities include a dramatic, planar-polarized collective cell migration in the Drosophila follicle that rotates the entire tissue. We are studying the origin and coordination of this migration, the molecular mechanisms that coordinate planar polarity in this ‘edgeless epithelium’, and how they create anisotropic biomechanical forces that shape the organ.
Figueroa-Clarevega A and D Bilder (2015). Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev Cell 33, 33:47-55. (cf commentary in Nature, Science Signaling, The Scientist)
Bunker BD, Nellimoottil TT, Boileau R, Classen AK, and D Bilder (2015). The Transcriptional Response to Tumorigenic Polarity Loss in Drosophila. eLife, Feb 26;4.
O’Brien LE and D Bilder (2013). Beyond the Niche: Tissue-level Coordination of Stem Cell Dynamics. Ann Rev Cell Dev Biol, 29: 107-36.
O'Brien LE, Soliman SS, Li X and D Bilder (2011). Altered Modes of Stem Cell Division Drive Adaptive Intestinal Growth. Cell, 147: 603-614. (cf commentary in Cell, Nature Reviews Molecular and Cell Biology, AAAS Science Podcast, NIH Radio)
Classen AK, Bunker BD, Harvey KF, Vaccari T, and D Bilder (2009), A tumor suppressor activity of Drosophila Polycomb genes mediated by JAK-STAT signaling. Nature Genetics, 41:1150-5. (cf commentary in Developmental Cell)
Vaccari T, Lu H, Kanwar R, Fortini M and D Bilder (2008). Endosomal Entry Regulates Notch Receptor Activation in Drosophila. Journal of Cell Biology, 180: 755-62
Lu H and D Bilder (2005). Endocytic control of epithelial polarity and proliferation in Drosophila. Nature Cell Biology, 7 (12): 1132-9. (cf commentary in Current Biology)
Vaccari T and D. Bilder (2005). The Drosophila tumor suppressor vps25 prevents non-autonomous overproliferation by regulating Notch trafficking. Developmental Cell, 9 (5): 687-98. (cf commentary in Current Biology)
Bilder D. (2004). Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes and Development 18: 1909-1925.
Photo credit: Mark Joseph Hanson of Mark Joseph Studio.
Last Updated 2015-08-27