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Research


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Research


The research in our group is centered on deciphering the mechanisms and nature of “morphomeostasis” (morphological tissue homeostasis) based on cell-cell interactions and cellular plasticity, through which tissue integrity and organ morphology are maintained throughout the life of a multicellular organism.

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The cellular communities organizing animal tissues have a remarkable ability to form and maintain a consistent morphology despite regular turnover of their constitutional units. This robust self-organizing system is an essential characteristic of multicellular animals. In this system, genetic signaling networks determine a transient mechanical state of cells and tissues, such as stretch or compression, through cell shape changes and tissue morphogenesis. At the same time, the mechanical state signals back to the genetic signaling network through mechanotransduction to form a signal transduction cycle. Once either the genetic or mechanical state experiences a modification, this genetic-mechanical-genetic signal transduction cycle transitions to another phase. This adaptably transitioning cycle is the underlying basis of tissue homeostasis, but it is not understood how the signal transduction cycle in each cell is coordinated to generate and maintain precise patterns of tissue morphology specific for each organ. Towards this aim, we have developed several model systems in fruit flies, Drosophila melanogaster, to dissect its molecular mechanisms.

Current research projects in the lab address mechanisms of cell competition, tissue repair and tumorigenesis primarily using Drosophila genetics, advanced microscopic techniques (confocal and electron microscopy), whole transcriptome analysis and dynamic modeling.

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Cell Competition


Cell Competition


Cell Competition = 細胞競合

Cell competition is observed in genetically heterogeneous tissues of multicellular organisms when neighboring cells have different cellular fitness.  Although what defines cellular fitness and how cells sense differences in cellular fitness are unclear, cellular growth rate and anabolic activity have been considered major factors to be compared between neighboring cells.  During cell competition, loser cells are normally viable when grown only with other loser cells; when they coexist with fitter winner cells, they are at a growth disadvantage and undergo apoptosis.  The region previously occupied by the loser cells is replaced by neighboring winner cells through compensatory proliferation of winner cells.  The mechanism underlying the phenomenon therefore not only assures sensing and elimination of potentially deleterious (e.g., precancerous) cells but is also tightly connected to the organ-size control system.

Compensatory cellular hypertrophy: the other strategy for tissue homeostasis.  Tamori, Y. and Deng, W.-M.  Trends in Cell Biology. 2014; 24, 230–237.

Tissue repair through cell competition and compensatory cellular hypertrophy in postmitotic epithelia.  Tamori, Y. and Deng, W.-M.  Developmental Cell. 2013; 25, 350363.

Cell competition and its implications for development and cancer.  Tamori, Y. and Deng, W.-M.  Journal of Genetics and Genomics. 2011; 38, 483–496.

Involvement of Lgl and Mahjong/VprBP in cell competition.  Tamori, Y., Bialucha, C.U., Tian, A.-G., Kajita, M., Huang, Y.-C., Norman, M., Harrison, N., Poulton, J., Ivanovitch, K., Disch, L., Liu, T., Deng, W.-M. and Fujita, Y.  PLoS Biology. 2010; 8, e1000422.

Mahjong-mediated regulation of cell competition.  Tamori, Y. and Deng, W.-M.  Experimental Medicine (Jikken Igaku). 2010; Vol. 29, No. 9 (Japanese).

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Tissue Repair


Tissue Repair


Tissue Repair = 組織修復

Metazoan tissues have the ability to maintain tissue size and morphology while eliminating aberrant or damaged cells.  In the tissue homeostasis system, cell division is the primary strategy cells use not only to increase tissue size during development but also to compensate for cell loss in tissue repair.  Our recent studies in Drosophila, however, have shown that cells in post-mitotic tissues undergo hypertrophic growth without division, contributing to tissue repair as well as organ development.  This “compensatory cellular hypertrophy” (CCH) is implemented by polyploidization through endoreplication cycle (endocycle), a variant cell cycle composed of DNA synthesis and gap phases without mitosis.  Indeed, similar hypertrophic cellular growth can be observed in different contexts such as Drosophila adult epidermis, mammalian hepatocytes or corneal endothelial cells.  We use Drosophila ovarian follicular epithelial cells as a model system to decipher the molecular mechanism of CCH.

Growth of winner cells in cell competition - replacement and compensation.  Tamori, Y.  Journal of Clinical and Experimental Medicine (Igaku No Ayumi). 2016; Vol. 29, No. 9 (Japanese).

Compensatory tissue repair in cell competition.  Tamori, Y.  Seitai No Kagaku. 2016; Vol. 67, No. 2 (Japanese).

Compensatory cellular hypertrophy: the other strategy for tissue homeostasis.  Tamori, Y. and Deng, W.-M.  Trends in Cell Biology. 2014; 24, 230–237.

Tissue repair through cell competition and compensatory cellular hypertrophy in postmitotic epithelia.  Tamori, Y. and Deng, W.-M.  Developmental Cell. 2013; 25, 350363.

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Tumorigenesis


Tumorigenesis


Tumorigenesis = 腫瘍形成

In epithelial tissues, cells communicate with their neighbors and receive information from the surrounding environment through signaling networks, adhesion molecules, and junctional molecules in order to form complex organs and to maintain their integrity and morphology.  This robust self-organizing system, however, is progressively disrupted during tumor development.  In tumorigenesis, transformed mutant cells evolve into a malignant neoplasm through a multistep process whereby the transformed cells acquire traits that enable them to become tumorigenic and ultimately malignant.  Although many genes have been identified as involved in different steps of cancer-cell progression, little is known about the beginning of tumorigenesis, in which mutant pro-tumor cells deviate from the robustly organized microenvironment to evolve into aggressive tumors.  We use Drosophila epithelial tissues as a model system to understand the initial steps of tumorigenesis.

Tissue-intrinsic tumor hotspots: terroir for tumorigenesis.  Tamori, Y. and Deng, W.-M.  Trends in Cancer. 2017; 3, 259–268.

Epithelial tumors originate in tumor hotspots, a tissue-intrinsic microenvironment.  Tamori, Y., Suzuki, E. and Deng, W.-M.  PLoS Biology. 2016; 14(9): e1002537.

Cell competition and its implications for development and cancer.  Tamori, Y. and Deng, W.-M.  Journal of Genetics and Genomics. 2011; 38, 483–496.

Involvement of Lgl and Mahjong/VprBP in cell competition.  Tamori, Y., Bialucha, C.U., Tian, A.-G., Kajita, M., Huang, Y.-C., Norman, M., Harrison, N., Poulton, J., Ivanovitch, K., Disch, L., Liu, T., Deng, W.-M. and Fujita, Y.  PLoS Biology. 2010; 8, e1000422.