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Research Introduction
Research 1. Development of medical treatments focusing on ploidy
In our laboratory, we are conducting research with the aim of developing new medical technologies that focus on cell ploidy.
Changes in ploidy are associated with various diseases, but cancer is particularly notable. Cancer is originally a disease caused by genomic abnormalities. Nearly 40% of human cancers (solid tumors) have undergone polyploidy (genome doubling), and it has been reported that the majority of lung and esophageal cancers undergo polyploidy during their development and progression. Polyploidized cancer cells are prone to chromosomal abnormalities during proliferation, and this state of proneness to chromosomal abnormalities (chromosomal instability) promotes the evolution of cancer, including metastasis and drug resistance. For this reason, recent large-scale studies using human cancer samples have revealed that polyploid cancers that have undergone genome doubling have a worse prognosis than diploid cancers.
In fact, our study using human liver cancer surgical specimens revealed that approximately 36% of liver cancers are polyploid, and that polyploid liver cancers show characteristic gene expression and histological images and have a significantly worse prognosis than polyploid liver cancers, making polyploidy a new marker for identifying a group of highly malignant liver cancers [British Journal of Cancer 2023]. In addition , we have developed a model that can easily determine the polyploidy of cancers from pathological images using artificial intelligence and predict the prognosis of cancers, which is currently difficult to determine [patent pending]. If this technology can be applied to clinical practice, it is expected that it will be possible to distinguish the characteristics of cancers based on their ploidy and consider treatments tailored to the characteristics.
In recent years , strategies have been developed to select treatment methods that match the genomic abnormalities in cancer cells, that is, the characteristics of cancer cells, rather than considering treatment methods based on the organ in which the cancer originated, such as for lung cancer and colon cancer. In this context, polyploid cancers and cancers that show chromosomal instability remain intractable cancers, for which there are still no specific treatments.
In particular, since all tissue stem cells that normally proliferate in the human body are diploid cells, and the active proliferation of polyploid cells is usually a cancer-specific phenomenon, if we could selectively inhibit the proliferation of only polyploid cells, it would be expected to become a treatment specific to polyploid cancers with fewer side effects. Therefore, we are currently conducting research from various perspectives to find the weaknesses of polyploid cancer cells. In the future, we aim to link this to the development of new treatments specific to polyploid cancers.
Research 2. Elucidation of polyploidy and pathology
In addition to cancer, it is known that polyploid cells increase in various tissue disorders such as liver cirrhosis, kidney disorders, and myocardial infarction, as well as with aging. However, the effect of polyploidy on the pathology of these diseases has not yet been fully elucidated. This is partly because little is known about the high frequency of polyploidy, and partly because there are few experimental tools available that are useful for research focusing on polyploidy.
Matsumoto has been conducting research focusing on the importance of polyploidy in the pathology of tissue injury and cancer. In the course of his research, he established a unique mouse model that visualizes the proliferation and behavior of polyploid cells by using multicolor reporter mice. He then clarified that polyploid cells, which were thought to be disadvantageous for cell proliferation, actively proliferate in chronically damaged livers and contribute to liver regeneration [Cell Stem Cell 2020]. Interestingly, he also demonstrated that hepatocytes can not only become polyploid but also reduce their ploidy (return to diploid cells) [Research Theme 3, Cell Stem Cell 2020]. It was found that the proliferation of polyploid hepatocytes contributes not only to chronic injury but also to maintaining normal liver homeostasis during the aging process [Cell Mol Gastroenterol Hepatol. 2021], but on the other hand, he also clarified that the proliferation of polyploid hepatocytes and the reduction of ploidy can cause carcinogenesis by increasing the frequency of chromosomal abnormalities [Nature Communications 2021].
Recent studies have shown that genomic damage often leads to polyploidy, that polyploid cells harbor more damage, and that polyploidy mitigates the effects of damage on cells [paper submitted].
Through further research, we hope to elucidate how polyploid cells behave during tissue injury and carcinogenesis, and how they affect surrounding cells, damaged organs, and the pathology of diseases.
Research 3. Elucidation of the mechanism of ploidy control and the significance of ploidy change
In the human body, some cells physiologically become polyploid, and as differentiated cells, cell proliferation usually stops. However, it is known that in myocardial infarction, polyploid cardiomyocytes contribute to myocardial regeneration by going through the cell cycle and becoming more polyploid. As described in Research Theme 2, it has also been revealed that hepatic cells maintain sustained proliferation ability even after becoming polyploid [Cell Stem Cell 2020] . Much of the control mechanism for the behavior of such polyploid cells and why some cells become polyploid in the first place remains unknown.
Matsumoto also revealed that polyploid cells reduce ploidy and become polyploid, which is involved in tissue regeneration and carcinogenesis [Cell Stem Cell 2020, Nature Communications 2021]. It has been common knowledge that in somatic cells other than reproductive cells, ploidy can increase but never decrease, and the ploidy reduction shown by Matsumoto overturns this common knowledge. However, interestingly, it has recently been found that such ploidy reduction also occurs in human cancer cells and fish skin, suggesting that ploidy reduction is a conserved event across species. It has also been reported that ploidy reduction in cancer cells is involved in drug resistance of cancer. We would like to solve the essential mysteries of polyploid cells, such as the molecular mechanisms involved in the control of polyploid cells, including the mechanism of ploidy reduction, which is still completely unknown, and what the benefits of polyploidization are in the first place.
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In addition to these studies, we are actively exploring various new research projects related to ploidy.
Please feel free to contact A if you’re interested in our latest reasearch.