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R. Folberg, C. Garcia, A.J. Maniotis; Invasive uveal melanoma morphogenesis is encoded by the three–dimensional features of extracellular matrix and cytoplasm . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1191.
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Purpose: It is generally assumed that histogenesis is regulated by genes. However, we have shown previously that the extracellular matrix (ECM) microenvironment can completely alter the types of tissue histogenesis patterns generated in vitro by both normal and cancer cells (Maniotis et al, 1997; 2002). Therefore, it is currently not possible to separate the contribution of gene expression in the formation of tissues, from the contribution of cytoplasmic structure, or ECM, in the formation of tissues. To separate nuclear control of histogenesis, from cytoplasmic or ECM control of histogenesis, we developed a novel method to generate tumor tissues with populations of tumor cells whose nuclei were removed. Methods: After nuclear removal low–invasive and high–invasive uveal melanoma cells, we exposed the living cytoplasts to varying 3–dimensional matrix conditions permissive for tumor–morphogenesis. Results: Normally, low invasive uveal melanoma cells form small spheroids in 3D matrices and high invasive uveal melanoma cells form looping patterns in the same matrix microenvironment. The type of histogenesis exhibited by different types of cytoplasts was identical to the histogenesis of the cytoplast's nucleated counterparts before enucleation. The resulting morphologies of the simple tissues constructed by the cytoplasts were also determined by the thickness and composition of matrix, and resembled the patterns generated by each type of cell's nucleated counterpart when 100 micron–thick laminin or Matrigel was used. Conclusions:Neither active transcription nor nuclei are required to specify the type of tissue patterning associated with poorly or highly invasive uveal melanoma cells. Instead, these different morphogenic expression patterns are specified by interactions between the cytoplasm and the 3–D ECM. These experiments also show that the instructions that specify normal and tumor histogenesis is activated by extracellular matrix attachment, is stored in the cytoplasm, and can be "remembered" by the cytoplasm even after placing cytoplasms in different environments.
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