We use Drosophila epithelia as model systems to elucidate mechanisms that respond to tissue disruption and those that restore tissue homeostasis. Epithelia need to respond to acute physiological stresses, such as loss of barrier integrity upon wounding or mechanical tension associated with tissue growth. However, epithelia also need to detect the presence of aberrant cells arising from mutagenic processes. Failure to detect and respond to these challenges in chronic stress, for example when cancerous cells continue to proliferate and disrupt tissue integrity. While cellular mechanisms mediating wound healing or tumor suppression in epithelia have received much attention, little is understood about stress responses at the level of entire tissues or about signaling cascades that distinguish acute from chronic stress conditions.
Signaling, regeneration and cancer
We address these open questions using in vivo wounding, regeneration and cancer models. Specifically, we investigate why wound responses and cancer are characterized by the same stress-responsive signaling signature, which prominently features the fly JNK/AP-1, JAK/STAT and Hippo/YAP(TAZ) pathways. We are investigating how cross talk between these pathways balances injury-induced apoptosis, cell survival and regenerative proliferation to successfully restore tissue homeostasis after injury.
We furthermore investigate signaling-to-chromatin pathways, which promote epigenetic adaptation to stress. One of the major challenges that we face is the ability to dissect stress-induced changes to gene regulation in very small cell populations in vivo. We are therefore working towards the establishment of cell-type specific genomic profiling by adapting DamID methods for in vivo applications.
We found that the juxtaposition of two cell populations with divergent fates induces enrichment of actomyosin at their entire shared cellular interfaces. We combined mathematical simulations with quantitative image analysis to demonstrate that interface contractility is necessary to eliminate single abberrantly specified cells from the tissue but that it is also sufficient to drive a host of morphogenetic behaviors such as cyst formation and cell segregation. Our results provided a novel perspective on the etiology of precancerous lesions arising from transcriptional heterogeneities between mutant and wild type cells. We now address how aberrantly specified cells are recognized by the surrounding epithelium and how contractile changes along the vertical axis of epithelial cells are regulated and coordinated.
Mechanics of cell shape transitions
While epithelial adhesion and polarity are well understood, almost nothing is known about the mechanics, let alone the cell biology, of epithelial morphogenesis along the squamous-cuboidal-columnar cell shape spectrum. We are currently building on our expertise to combine mathematical modeling with quantitative imaging to elucidate the cell-biological basis of force generation during cell shape transitions. To this end we investigate the cuboidal-squamous and cuboidal-columnar shape transitions of follicle epithelai that occur in the context of egg chamber growth. Our studies aim to begin to understand the origin of fundamental cell shapes arising in any epithelial tissue that are specific to protective, absorptive or secretory functions.