During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called "cell competition" (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis. Here, we combined live imaging analyses of two different oncogenic clones (Yki/YAP activation and Ras activation) in the Drosophila epithelium with computer simulation of tissue mechanics to elucidate such a mechanism. Contrary to the previous expectation that cell volume loss after apoptosis of loser cells was simply compensated for by the faster proliferation of winner cells, we found that the lost volume was compensated for by rapid cell expansion of winners. Mechanistically, the rapid winner-dominated cell expansion was driven by apoptosis-induced epithelial junction remodeling, which causes re-connection of local cellular connectivity (cell topology) in a manner that selectively increases winner apical surface area. In silico experiments further confirmed that repetition of loser elimination accelerates tissue-scale winner expansion through topological changes over time. Our proposed mechanism for linking loser death and winner expansion provides a new perspective on how tissue homeostasis disruption can initiate from an oncogenic mutation.
BackgroundSeveral lines of evidence associate misregulated genetic expression with risk factors for diabetes, Alzheimer’s, and other diseases that sporadically develop in healthy adults with no background of hereditary disorders. Thus, we are interested in genes that may be expressed normally through parts of an individual’s life, but can cause physiological defects and disease when misexpressed in adulthood.ResultsWe attempted to identify these genes in a model organism by arbitrarily misexpressing specific genes in adult Drosophila melanogaster, using 14,133 Gene Search lines. We identified 39 “reduced-lifespan genes” that, when misexpressed in adulthood, shortened the flies’ lifespan to less than 30% of that of control flies. About half of these genes have human orthologs that are known to be involved in human diseases. For about one-fourth of the reduced-lifespan genes, suppressing apoptosis restored the lifespan shortened by their misexpression. We determined the organs responsible for reduced lifespan when these genes were misexpressed specifically in adulthood, and found that while some genes induced reduced lifespan only when misexpressed in specific adult organs, others could induce reduced lifespan when misexpressed in various organs. This finding suggests that tissue-specific dysfunction may be involved in reduced lifespan related to gene misexpression. Gene ontology analysis showed that reduced-lifespan genes are biased toward genes related to development.ConclusionsWe identified 39 genes that, when misexpressed in adulthood, shortened the lifespan of adult flies. Suppressing apoptosis rescued this shortened lifespan for only a subset of the reduced-lifespan genes. The adult tissues in which gene misexpression caused early death differed among the reduced-lifespan genes. These results suggest that the cause of reduced lifespan upon misexpression differed among the genes.
Cell populations in multicellular organisms show genetic and non-genetic heterogeneity, even in undifferentiated tissues of multipotent cells during development and tumorigenesis. The heterogeneity causes difference of mechanical properties, such as, cell bond tension or adhesion, at the cell–cell interface, which determine the shape of clonal population boundaries via cell sorting or mixing. The boundary shape could alter the degree of cell–cell contacts and thus influence the physiological consequences of sorting or mixing at the boundary (e.g., tumor suppression or progression), suggesting that the cell mechanics could help clarify the physiology of heterogeneous tissues. While precise inference of mechanical tension loaded at each cell–cell contacts has been extensively developed, there has been little progress on how to distinguish the population-boundary geometry and identify the cause of geometry in heterogeneous tissues. We developed a pipeline by combining multivariate analysis of clone shape with tissue mechanical simulations. We examined clones with four different genotypes within Drosophila wing imaginal discs: wild-type, tartan (trn) overexpression, hibris (hbs) overexpression, and Eph RNAi. Although the clones were previously known to exhibit smoothed or convoluted morphologies, their mechanical properties were unknown. By applying a multivariate analysis to multiple criteria used to quantify the clone shapes based on individual cell shapes, we found the optimal criteria to distinguish not only among the four genotypes, but also non-genetic heterogeneity from genetic one. The efficient segregation of clone shape enabled us to quantitatively compare experimental data with tissue mechanical simulations. As a result, we identified the mechanical basis contributed to clone shape of distinct genotypes. The present pipeline will promote the understanding of the functions of mechanical interactions in heterogeneous tissue in a non-invasive manner.
Biological systems are inherently noisy; however, they produce highly stereotyped tissue morphology. Drosophila pupal wings show a highly stereotypic folding through uniform expansion and subsequent buckling of wing epithelium within a surrounding cuticle sac. The folding pattern produced by buckling is generally stochastic; it is thus unclear how buckling leads to stereotypic tissue folding of the wings. We found that the extracellular matrix (ECM) protein, Dumpy, guides the position and direction of buckling-induced folds. Dumpy anchors the wing epithelium to the overlying cuticle at specific tissue positions. Tissue-wide alterations of Dumpy deposition and degradation yielded different buckling patterns. In summary, we propose that spatio-temporal ECM remodeling shapes stereotyped tissue folding through dynamic interactions between the epithelium and its external structures.
When two types of clonal cell populations competitively grow in epithelial tissues, only at the boundary between the two clones, apoptosis selectively occurs in the cells with lower division rate. Although genetic studies have suggested that F-actin dependent mechanical force is a major regulator of cell competition, how the difference of division rates affects the mechanical force is little investigated. Using the cell vertex model, we numerically found that the boundary of the clones was more smoothly rounded only as the difference of division rates increases. This boundary shape is consistent with experiments in Drosophila. Moreover, the slower dividing cells exhibited boundary-specific abnormalities not only in cell shape, but also in tensile force. 3P273ENaC 細胞内動態の数理モデル構築による上皮 Na + 輸送制御 解析 Epithelial Na + channels (ENaC) are translocated to the apical cell membrane from the intracellular store site. Experimental observations on ENaC-mediated Na + transport indicate that at least following 4 steps are involved in ENaC translocation: i.e. 1) insertion, 2) endocytosis, 3) recycling, and 4) degradation.To understand more details about regulation of Na + transport in epithelial cells and which state is the rate-limiting one, we applied a mathematical model including 4 steps for electrophysiological parameter of Na + transport, suggesting that the amount of recycled ENaCs depends on quality control of ENaC in the intracellular store site. This means that this model leads us to novel understandings on ENaC-mediated Na + transport. 3P274 真性粘菌 Physarum polycephalum とそのモデルによる錯視の 計算 Computing visual illusion by Physarum plasmodium and the model True slime mold Physarum polycephalum plasmodium is a huge unicellular amebic organism. It is widely used in biocomputing studies. However, the most of these studies used plasmodium as optimization calculator. By contrast, we propose Physarum biosensor element that duplicate human KANSEI/feeling information. We show Physarum plasmodium and our asynchronous cellular automata model are able to "calculate" visual illusions such as subjective contour of Kanizsa's triangle and Muller-Lyer illusion. 3P275 錯視を引き起こす図形パターンに対する真性粘菌変形体の 反応 Behavior of the physarum plasmodium to the graphical pattern that provide the optical illusionThe plasmodium of Physarum polycephalum is a giant acellular organism that crawls on planar surfaces foraging food sources and forms a network of protoplasmic tubes connecting the masses of protoplasm at the food sources. In this study, we investigated the behavior of the plasmodium to the graphical food sources arranged in the pattern that provide the optical illusion Kanizsa triangle. We found that such graphical patterns have an effect on the plasmodium same as optical illusion in terms of connecting tube network between food sources. Moreover, in this experiments, we introduced the epochal material of food source made from nutrient rich agar, which is easily-shaped into various figures and sizes. 3P276 概日中枢時計のウエーブパターンとその機能についてWave-like structure and its func...
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