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Research Introduction
Research 1. Development of medical treatments focusing on ploidy
Our laboratory is dedicated to developing innovative medical technologies that focus on cellular ploidy, with the goal of creating new therapeutic strategies to overcome treatment-resistant cancers.
■Unresolved link between ploidy and cancer
Cancer arises from genomic abnormalities. More than a century ago, it was proposed that cancer cells often undergo polyploidization (whole-genome doubling), and that such events might play a critical role in tumor initiation. However, compared to studies focusing on gene mutations or epigenetic alterations, research addressing the role of ploidy in cancer remains scarce.
With the progress of cancer genome analyses, it has become evident that nearly 40% of all human solid tumors have experienced polyploidization (whole-genome doubling). In particular, more than half of lung and esophageal cancers undergo such events during tumor development or progression. Large-scale pan-cancer analyses have revealed that polyploidized cancers tend to harbor extensive chromosomal abnormalities and are associated with poor prognosis. Nonetheless, how polyploidization contributes to disease pathology in individual cancers and what specific vulnerabilities polyploid cancers possess remain largely unknown.
■Identifying Aggressive Cancers through Ploidy-Based Stratification
We have developed a range of original research tools—including cultured cell systems, mouse models, and ploidy assessment techniques—to advance the study of cellular ploidy and its link to cancer pathophysiology. As described below, Matsumoto established a mouse model that enables in vivo visualization of polyploid cells [Cell Stem Cell 2020, PMID 31866222]. Using this model, we demonstrated that polyploid hepatocytes serve as a critical cell of origin for liver cancer, and that during hepatocarcinogenesis derived from polyploid hepatocytes, cellular ploidy changes dynamically. We also showed that fluctuations in ploidy accelerate chromosomal instability and promote tumorigenesis [Nature Communications 2021, PMID 33510149].
Furthermore, our analysis of human liver cancer specimens provided detailed insights into the characteristics of polyploid hepatocellular carcinoma (HCC) [British Journal of Cancer 2023, PMID 37715023]. Chromosomal FISH analysis revealed that approximately 36% of HCCs are highly polyploid. These polyploid HCCs frequently display distinct pathological features, such as a macrotrabecular-massive growth pattern and abundant polyploid giant cancer cells (PGCCs). We also identified that UBE2C, a ubiquitin-conjugating enzyme highly expressed during mitosis, is markedly upregulated in polyploid HCC. The presence of PGCCs and elevated UBE2C expression serve as indicators of polyploid HCC and as potential markers for poor prognosis. Consistent with findings from pan-cancer analyses, these results demonstrate that high ploidy correlates with increased malignancy, identifying polyploid HCC as a subgroup of treatment-resistant liver cancers.
Based on these findings, the ability to easily assess tumor ploidy could enable early identification and aggressive management of high-risk cancers, thereby facilitating personalized cancer therapy. However, current methods for evaluating ploidy—such as genomic sequencing, flow cytometry, and chromosomal FISH—require complex analyses, limiting their clinical applicability. To address this challenge, we have developed an artificial intelligence model that can accurately assess polyploidization and predict prognosis directly from routine pathological images [Japanese Patent Application 2024-26830; PCT/JP2024/044155; Communications Medicine 2025, PMID 40610763]. This technology holds promise for clinical implementation, allowing cancer diagnosis and treatment planning based on ploidy status.
Previous pan-cancer analyses have classified tumors according to whether they have undergone polyploidization, showing that such cancers generally have poor prognosis. In contrast, our studies emphasize that the current level of tumor ploidy, rather than a past history of genome doubling, correlates more strongly with cancer aggressiveness. Importantly, this relationship between high ploidy and malignancy has also been observed in other cancers (manuscript in preparation). Since ploidy is presumed to be particularly plastic in cancer cells, our findings underscore the importance of assessing tumor ploidy itself, rather than merely its history of polyploidization.
■How Do Polyploid Cancers Arise and Why Are They Highly Malignant?
Why do some cancers undergo polyploidization, and why are polyploid cancers particularly aggressive? The latter question is thought to be closely linked to chromosomal instability (CIN). Because polyploid cells contain extra sets of chromosomes, they are inherently prone to chromosome mis-segregation during mitosis. This tendency increases the likelihood of chromosomal abnormalities, a condition known as chromosomal instability. CIN generates genomic diversity among cancer cells, which accelerates cancer evolution. Consequently, polyploid cancers more readily produce highly malignant subclones—cells with enhanced proliferative capacity, resistance to anticancer drugs, and metastatic potential.
Our recent studies suggest that, in addition to promoting CIN, polyploidization also contributes to malignancy by conferring resistance to genomic damage. Polyploidization and genomic injury are intimately connected: polyploid cancer cells harbor more genomic damage than diploid cells, yet their redundant genomes allow them to buffer the detrimental effects of such damage. For instance, we found that polyploid cells exhibit increased resistance to genotoxic anticancer drugs that kill cells by inducing DNA damage [Cell Death Discovery 2024, PMID 39397009]. Thus, polyploid cells can persist despite extensive genomic injury, serving as “reservoirs of genomic damage” that drive cancer initiation and progression.
■Exploring Therapeutic Targets Selective for Polyploid Cancers
Precision medicine aims to identify genomic alterations that define cancer properties and to select the most effective treatments based on those alterations. Polyploid cancers—known for poor prognosis—represent one of the most urgent challenges in oncology, yet no therapies have been developed that specifically target them.
In the human body, certain cell types physiologically undergo polyploidization; however, these differentiated polyploid cells typically cease proliferation. Persistent and active proliferation of polyploid cells occurs almost exclusively in cancers. Therefore, understanding the mechanisms that enable polyploid cells to re-enter the cell cycle and identifying vulnerabilities specific to proliferating polyploid cells could lead to selective and effective treatments for polyploid cancers.
To this end, we are conducting research aimed at developing therapies that selectively target polyploid cancers. Using esophageal adenocarcinoma as a model, we have recently identified key molecular mechanisms that allow polyploid precancerous cells to initiate proliferation (manuscript in preparation). This discovery could pave the way for novel therapeutic strategies that prevent carcinogenesis driven by polyploidization. In addition, we are pursuing multiple approaches to identify unique weaknesses of polyploid cancer cells, with the long-term goal of establishing new treatment modalities specifically targeting polyploid cancers.
Research 2. Elucidation of polyploidy and pathology
Polyploid cells are known to increase not only in cancers but also in various pathological conditions such as liver cirrhosis, kidney injury, and myocardial infarction, as well as during aging. However, how polyploidization influences the pathophysiology of these disorders remains largely unexplored. This is partly because the high prevalence of polyploidization itself has not been widely recognized, and because few experimental tools are available to study diseases from the perspective of cellular ploidy.
Beyond cancer research, Matsumoto has been investigating the significance of ploidy changes in tissue injuries, particularly in the liver. Using multicolor reporter mice, we established an original mouse model that enables visualization of polyploid cell proliferation and behavior in vivo. This model revealed that, contrary to previous assumptions that polyploid cells have limited proliferative capacity, polyploid hepatocytes actively proliferate in chronically damaged livers and contribute to liver regeneration [Cell Stem Cell 2020, PMID 31866222]. Furthermore, polyploid hepatocytes were also shown to play a role in maintaining liver homeostasis during aging [Cell Mol Gastroenterol Hepatol 2021, PMID 33359651].
The liver is a unique organ with remarkable regenerative capacity, but in other organs, the roles and significance of polyploid cells remain poorly understood. Our goal is to elucidate how physiologically or pathologically induced polyploid cells behave within different tissues, and how they influence organ responses to injury and the progression of various diseases.
Research 3. Elucidation of the mechanism of ploidy control and the significance of ploidy change
Through analyses using our original mouse model that enables visualization of polyploid cell proliferation and behavior, Matsumoto discovered that polyploid cells can reduce their ploidy to become diploid again, a process that contributes to both tissue regeneration and tumorigenesis [Cell Stem Cell 2020, PMID 31866222; Nature Communications 2021, PMID 33510149]. Traditionally, it has been believed that while somatic cells may increase their ploidy, they do not decrease it. Therefore, the finding that somatic cells can undergo ploidy reduction, subsequently proliferate, and participate in regeneration or carcinogenesis was an unexpected and striking discovery.
Interestingly, recent studies have shown that ploidy reduction can also occur in human cancer cells, mouse embryonic stem cells, and fish epidermal cells, suggesting that this phenomenon is evolutionarily conserved across species. Moreover, in cancer cells, ploidy reduction has been implicated in the acquisition of drug resistance. Nevertheless, the molecular mechanisms that enable ploidy reduction remain almost entirely unknown.
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Our goal is to uncover the fundamental biology of how ploidy reduction occurs and how cellular ploidy is regulated. By elucidating these mechanisms, we aim to reveal the essential principles governing polyploid cells and their roles in tissue regeneration and disease development.
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.