Collective cell behavior …
… in tissue injury
The restoration of homeostasis after tissue damage relies on proper spatial-temporal control of distinct cell behaviors. My lab is particularly interested in how the intricate balance between proliferation and cell death at wound sites is controlled. In Drosophilaimaginal discs, this balance is coordinated by the conserved TNFa/JNK/AP-1, Cytokine/JAK/STAT and Hippo/Yki signaling pathways. We recently demonstrated that cells at wound sites undergo a JNK-induced cell cycle arrest in G2 (Cosolo et al., 2019). Surprisingly, this reversible arrest induces senescent properties, such as resistance to apoptosis and expression of mitogenic cytokines. Importantly, on transient timescales this reversible G2-arrest protects cells in the wound from apoptosis. However, in chronic stress conditions, it reduces the proliferative potential of wound-associated cells whilst promoting non-autonomous overgrowth, combined establishing a chronic wound phenotype. Strikingly, we identify G2-arrested cells in tumor models where their senescent qualities contribute to the oncogenic potential of the tumor microenvironment. We thus propose that transient cell cycle stalling with senescent features has key roles in wound healing but becomes detrimental upon chronic stress signaling. Combined, our work has important implications for our understanding of tissue repair and importantly, for our understanding of chronic wound healing pathologies and tumorigenic transformation.
… in the presence of aberrant cells
Because of their exposed position, epithelia are susceptible to mutagenesis. As a consequence, genetically altered or transformed cells arise at a constant rate in epithelial tissues. Typically, elimination of these cells from an organism has been attributed to immunosurveillance mechanisms. More recently, tissue-intrinsic surveillance mechanisms – cell competition, intra-epithelial tumor suppression or epithelial defense against cancer (EDAC) – driving elimination of aberrant cells have been described. These processes share two striking feature: (1) the elimination of aberrant cells is driven by surrounding wild type cells and (2) elimination requires cell contact between normal and eliminated cells. My lab established a paradigm, in which aberrantly-specified and RasV12-transformed cells are detected by a tissue intrinsic surveillance mechanism that we termed interface contractility (Bielmeier et al., 2016). Combining experimental and mathematical modeling approaches, we demonstrated that interfacial actomyosin contractility eliminates aberrantly-specified cells from the tissue. We are currently investigating which cell biological mechanisms and signaling pathways mediate recognition and elimination of aberrantly specified cells. Revealing recognition and elimination strategies is crucial to understand how transformed cells may evade these intra-epithelial tumor suppression mechanisms and how these strategies may become therapeutic targets.
… in tissue mechanics
Columnar, cuboidal and squamous shapes convey basic epithelial functions, such as absorption, secretion and protection, but their morphogenetic principles in health and disease are not understood. We analyze these principles in the follicle epithelium of the growing Drosophila egg chamber, where cells transition dynamically through these shapes. We recently described that how actomyosin and adherens junctions architecture remodels during stages of germline growth (Balaji et al., 2019). A balance between junctional relaxation and locally reinforced apical contractility protect barrier integrity of the epithelium while at the same time protecting a population of cuboidal cells from expanding their apical surface and thus flattening, as the germline surface expands. Failure to resist flattening causes egg chamber rounding and degeneration. Our current work focusses on a cell population in the follicle epithelium which undergoes developmentally regulated flattening, and for which the contribution of cell-intrinsic and extrinsic forces has not been dissected. Our work thus provides insight into how epithelial cell adhesion and cytoskeletal dynamics balance internal and external forces to establish cell, tissue and organ shape in vivo.