Aneuploidy is a ubiquitous feature of cancer cells, and accumulation of aneuploidy is believed to often happen via tetraploidization (genome doubling) as an intermediate step. This idea is based on the observations that nearly 40% of all tumors have likely undergone whole genome duplication during their clonal evolution, that tetraploidy was shown to buffer chromosomal instability (CIN), and that tetraploid (4N), but not diploid (2N), mammary epithelial cells could induce subcutaneous tumors in nude mice. A widely accepted model suggests that the extra centrosomes commonly arising during tetraploidization are responsible for ongoing chromosome missegregation during mitosis leading to the accumulation of aneuploidy and CIN. A possible selective advantage conferred by aneuploidy would, in turn, promote tumorigenesis. Support for this model comes from the fact that both aneuploidy and supernumerary centrosomes have been observed in human tumors and that extra centrosomes can promote tumorigenesis in animal models. However, recent reports have shown that cells kept in standard culture conditions spontaneously lose extra centrosomes acquired during tetraploidization, and that this centrosome loss can occur over a very short time period (about two weeks). The discrepancies between what is believed to happen in vivo and what is observed in standard tissue culture conditions suggests that the in vivo ecological niche (e.g., various factors within the tumor microenvironment) can impose specific selective pressures that influence the evolution of 4N cells, and thus the consequences of tetraploidization. This hypothesis will be tested by experimentally inducing tetraploidy and then combining a multi-disciplinary approach to study the interplay between altered ploidy/centrosome number and the microenvironment in three specific research aims.
The first aim will determine the effects of the physico- chemical microenvironment on the evolution of 4N cells and will identify specific, physiologically relevant, physico-chemical properties of the microenvironment that produce an evolved cell population unlike the one emerging in standard culture conditions.
The second aim will establish how communication with stromal cells influences the evolution of 4N epithelial cells and specifically assess the role of signaling molecules and cell- cell physical interactions in shaping the evolution of cells with altered ploidy.
The third aim will identify the key processes driving the evolution of 4N cells in vivo. This will be achieved by injecting newly formed 4N cells in mouse models and then characterizing the evolved, tumor-derived cell population. An ODE-based mathematical model will be used in each aim to capture the evolution dynamics of subpopulations of cells with defined ploidies and centrosome numbers and pinpoint the events, cellular processes, and microenvironmental factors that drive the differential, context-dependent, evolutionary outcomes. The findings from these studies will not only broaden the current knowledge, but also set the stage for future identification of potential molecular targets and/or novel microenvironment manipulations for cancer therapy.

Public Health Relevance

Tetraploidization (doubling of the genome) has been proposed to promote tumorigenesis due to the concomitant acquisition of extra centrosomes (key organelles for cell division) during the tetraploidization process. However, this is inconsistent with recent evidence that newly formed tetraploid cells rapidly lose their extra centrosomes, suggesting that the evolution of tetraploid cells may be influenced by specific conditions present in the native tissue and/or in the tumor microenvironment. This project will investigate this possibility by integrating experimental approaches and mathematical modeling to determine which events, cellular processes, and microenvironmental factors are important for the evolution and tumorigenic potential of tetraploid cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Gindhart, Joseph G
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Virginia Polytechnic Institute and State University
Schools of Arts and Sciences
United States
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