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Research Achievements

​2026年
To evaluate tumor ploidy at the single-cell level, we performed chromosome fluorescence in situ hybridization (FISH) and investigated the significance of tumor ploidy in human intrahepatic cholangiocarcinoma. We found that higher tumor ploidy was strongly associated with greater intratumoral heterogeneity. Moreover, highly polyploid tumors exhibited greater aggressiveness and a more immunosuppressive tumor microenvironment than low-ploidy (near-diploid) tumors. Highly polyploid tumors also tended to contain cancer cells with larger nuclei, as reflected by increased nuclear diameter and area, and were enriched for polyploid giant cancer cells (PGCCs), a population of cancer cells with markedly enlarged nuclei that has been associated with poor prognosis in several other cancer types. These findings suggest that pathological assessment focusing on cancer cell nuclear morphology may provide a useful approach for predicting prognosis and guiding treatment decisions in patients with intrahepatic cholangiocarcinoma.
  • Matsumoto T. Cell Fusion-Mediated Induction of Polyploidy, Aneuploidy, and Genomic Instability in Cancer Cells. Advances in Experimental Medicine and Biology. 1509: 301–317. (2026) https://doi.org/10.1007/978-3-032-22637-2_11
 
In this study, we comprehensively characterized the spatial distribution and subtype composition of cancer-associated fibroblasts (CAFs) in human pancreatic cancer by analyzing tumors with diverse histopathological features in an unbiased spatial manner. We found that senescent CAFs, which exhibit features of cellular senescence, are preferentially localized at the invasive front of pancreatic tumors. Moreover, a greater accumulation of these senescent CAFs was associated with more advanced disease and poorer patient prognosis. These senescent CAFs highly expressed marker genes of both myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs), suggesting that they represent a distinct CAF population with hybrid characteristics. They were also suggested to secrete high levels of tumor-promoting factors, including CCN2 and PLAU. These findings provide new insights into the spatial heterogeneity of the pancreatic tumor microenvironment and may contribute to the development of novel therapeutic strategies targeting stromal cell populations.
2025
  • Matsumoto, Tomonori. "In vivo dynamics of polyploid cells and their involvement in liver cancer pathogenesis." Experimental Medicine, Vol. 43, No. 16, 2583-2586 (2025.10)
  • Ogawa Y, Fisher L, Matsumoto T*. The Impact of Polyploid Giant Cancer Cells: The Root of Stress Resilience. Cancer Sci. (2025) Nov;116(11):2949-2958.
       https://doi.org/10.1111/cas.70191

  • Ferreira-Gonzalez S, Matsumoto T, Hara E, Forbes SJ. Senescence, aging and disease throughout the gastrointestinal system. Gastroenterology. (2025) , 169(7):1357-1379. https://doi.org/10.1053/j.gastro.2025.06.010​​​

  • Okumura S, Konishi Y, Kitano T, Matsumoto T, Obama K, Nagayama S, Hara E. Refining the Feasibility of Machine-Learning-Based Diagnostic Model Utilizing Gut Microbiota Analysis for Colorectal Cancer Screening. Cancer Medicine. (2025) Jul;14(13):e70935. https://doi.org/10.1002/cam4.70935
  • Matsuura T, Abe M, Harada Y, Kido M, Nagahara H, Kodama Y, Ueda Y, Hara E, Niioka H*, Matsumoto T*. Selective identification of polyploid hepatocellular carcinomas with poor prognosis by artificial intelligence-based pathological image recognition. Communications Medicine. 5: 270. (2025)  https://doi.org/10.1038/s43856-025-00967-8

We developed an image classification model to determine the ploidy status of hepatocellular carcinoma (HCC) from hematoxylin and eosin (HE)-stained pathological images. To achieve this, we trained a deep learning algorithm using teacher data derived from diploid and polyploid HCC cases, as defined by chromosomal FISH. The constructed AI model was further validated with public databases and was able to reliably determine tumor ploidy from pathological images. Importantly, ploidy assessment by this AI model enabled the identification of HCC cases with poor prognosis. The AI-based tumor ploidy classification is expected to serve as a valuable diagnostic tool for advancing personalized medicine focused on tumor ploidy.

  • Kitano T, Okumura S*, Matsumoto T*, Tsunoda S, Nishigori T, Obama K, Hara E. The involvement of oral pathogenic bacteria, Fusobacterium nucleatum subspecies animalis in the pathogenesis of human esophageal adenocarcinoma. Gastro Hep Advances. 4(7):100660. (2025).
    https://doi.org/10.1016/j.gastha.2025.100660
2024年
2024

  • Matsumoto,T "The Relationship Between Polyploidization and Cellular Aging"Experimental Medicine　Vol.42 No.20, 3152-3157 (2024.12)

  • Hayashi K, Horisaka K, Harada Y, Ogawa Y, Yamashita T, Kitano T, Wakita M, Fukusumi T, Inohara H, Hara E*, Matsumoto T*. Polyploidy mitigates the impact of DNA damage while simultaneously bearing its burden. Cell Death Discov. 10(1), 436. (2024)​

​https://www.fbs.osaka-u.ac.jp/en/research_results/papers/detail/1093

We generated polyploid cell lines and compared DNA damage accumulation between polyploid and diploid cells using various experimental approaches. Our findings revealed that polyploidization is closely linked to DNA damage induction, making polyploid cells more susceptible to DNA damage. However, at the same time, these cells can mitigate its impact and survive. Indeed, when we treated diploid and polyploid cells with anticancer agents that kill cancer cells by inducing DNA damage, polyploid cells accumulated more DNA damage yet exhibited greater resistance to the drugs than diploid cells. Furthermore, gene expression changes associated with DNA damage were attenuated in polyploid cells. These characteristics of polyploid cells may contribute to the resistance of polyploidized cancers to chemotherapy.

  • Matsumoto , T. and Hara, E. "Cellular senescence and cancer." Cancer and Chemotherapy, Vol. 51, No. 8, 781-785 (2024)

  • Abe S, Masuda A*, Matsumoto T* , Inoue J, Toyama H, Sakai A, Kobayashi T, Tanaka T, Tsujimae M, Yamakawa K, Gonda M, Masuda S, Uemura H, Kohashi S, Inomata N, Nagao K, Harada Y , Miki M, Irie Y, Juri N, Ko T, Yokotani Y, Oka Y, Ota S, Kanzawa M, Itoh T, Imai T, Fukumoto T, Hara E, Kodama Y. Impact of intratumoral microbiome on tumor immunity and prognosis in human pancreatic ductal adenocarcinoma. J Gastroenterol . 59(3), 250-262. (2024)

  • Matsumoto, T. and Hara, E. "Cellular senescence and malignant tumors." Japanese Clinical Journal . 82(1). (2024)​

2023年
2023

  • Matsuura T , Ueda Y, Harada Y , Hayashi K , Horisaka K , Yano Y, So S, Kido M, Fukumoto T, Kodama Y, Hara E, Matsumoto T* . Histological diagnosis of polyploidy discriminates an aggressive subset of hepatocellular carcinomas with poor prognosis. Bri J Cancer. 129(8), 1251-1260. (2023)​​​

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Human solid tumors are frequently polyploid, but the characteristics of polyploid cancer have not been well elucidated. In this study, we evaluated the ploidy of human hepatocellular carcinoma by chromosome FISH and found that approximately 36% of hepatocellular carcinomas are polyploid. We also found that polyploid hepatocellular carcinomas exhibit characteristic pathological structures, including the presence of polyploid giant cancer cells, as well as highly malignant properties. Furthermore, by transcriptome analysis, we identified a molecular marker for polyploid hepatocellular carcinoma, the ubiquitin E2 binding molecule UBE2C. This study revealed that polyploidy is a new cancer genome characteristic that defines a group of cancers with poor prognosis, and provides insights that will serve as the foundation for new personalized cancer medicine, in which prognosis prediction and treatment are performed from the perspective of polyploidy.

  • Matsudaira T*, Nakano S, Konishi Y, Kawamoto S, Uemura K, Kondo T, Sakurai K, Ozawa T, Hikida T, Komine O, Yamanaka K, Fujita Y, Yamashita T, Matsumoto T , Hara E*. Cellular senescence in white matter microglia is induced during aging in mice and exacerbates the neuroinflammatory phenotype. Commun Biol . 6(1), 665. (2023)

 

  • Kawamoto S#*, Uemura K#, Hori N, Takayasu L, Konishi Y, Katoh K, Matsumoto T , Suzuki M, Sakai Y, Matsudaira T, Adachi T, Ohtani N, Standley DM, Suda W, Fukuda S, Hara E *. Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota. Nat Cell Biol . 25(6), 865-876. (2023)

 

  • Matsumoto, Tomokuni , Hara, Eiji. "Microbiome, aging, and senolytics." Hepato-Biliary-Pancreatic. 86(3), 305-310. (2023)

 

  • Matsumoto, Tomokuni , Hara, Eiji. "Cellular senescence and individual aging." Geriatric Medicine . 61(1), 23-28. (2023)

2022年
2022

  • Matsumoto T* . Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers. Int J Mol Sci . 23(16), 9409. (2022)

  • Konishi Y, Okumura S, Matsumoto T , Itatani Y, Nishiyama T, Okazaki Y, Shibutani M, Ohtani N, Nagahara H, Obama K, Ohira M, Sakai Y, Nagayama S, Hara E*. Development and evaluation of a colorectal cancer screening method using machine learning-based gut microbiota analysis. Cancer Med . 11(16), 3194-3206. (2022)

  • Tsuji S, Minami S, Hashimoto R, Konishi Y, Suzuki T, Kondo T, Sasai M, Torii S, Ono C, Shichinohe S, Sat S, Wakita M, Okumura S, Nakano S, Matsudaira T, Matsumoto T , Kawamoto S , Yamamoto M, Watanabe T, Matsuura Y, Takayama K, Kobayashi T, Okamoto T, Hara E*. SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response. Nat Aging . 2(2) , 115-124. (2022)

  • Kawamoto S, Matsumoto T , Takasugi M, Hara E. The 6th international cell senescence association conference. Genes Cells . 27(8). 517-525. (2022)

2021年
2021

  • Matsumoto T * , Wakefield L, Grompe M. The Significance of Polyploid Hepatocytes During Aging Process. Cell Mol Gastroenterol Hepatol . 11(5), 1347-1349. (2021)​

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In this study, we  clarified that polyploid hepatocytes are the origin of regeneration in hepatocyte turnover during normal aging process.

  • Okumura S#, Konishi Y#, Narukawa M#, Sugiura Y, Yoshimoto S, Arai Y, Sato S, Yoshida Y, Tsuji S, Uemura K, Wakita M, Matsudaira T, Matsumoto T , Kawamoto S, Takahashi A, Itatani Y, Miki H, Takamatsu M, Obama K, Takeuchi K, Suematsu M, Ohtani N, Fukunaga Y, Ueno M, Sakai Y, Nagayama S, Hara E*. Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion. Nat Commun . 12(1), 5674. (2021)

  • Matsumoto T* , Wakefield L, Peters A, Peto M, Spellman P, Grompe M*. Proliferative polyploid cells give rise to tumors via ploidy reduction. Nat Commun . 12(1), 646. (2021)

In this study, we clarified a new carcinogenic mechanism, revealing that polyploid hepatocytes proliferating during liver regeneration are an important source of liver cancer and that the reduction in ploidy that occurs during this process acts as a driver of carcinogenesis. The "reduction in ploidy" revealed in a previous paper (Cell Stem Cell 2020) is thought to lead to chromosome segregation abnormalities and carcinogenesis due to the complex chromosome distribution. Our current research demonstrates that ploidy reduction occurs frequently during hepatocarcinogenesis in mice, promoting the induction of chromosome abnormalities. Interestingly, we also found that hepatocytes that proliferate stably as polyploid cells lose the ability to reduce ploidy, which suppresses carcinogenesis mediated by ploidy reduction. These findings suggest that the proliferation of polyploid cells and reduction in ploidy could be effective therapeutic targets for preventing carcinogenesis.

  • Matsumoto , T. and Hara, E. "Mechanism and treatment strategy of obesity-related hepatocarcinogenesis centered on cellular senescence " Experimental Medicine . 39(5), 721-5. (2021)

 

  • Matsumoto, Tomonori *. "Postdoctoral study abroad: there's always something to discover!" Experimental Medicine . 39(1), 124-7. (2021)

2020年
2020

  • Matsumoto T *, Wakefield L, Tarlow BD, Grompe M*. In vivo lineage tracing of polyploid hepatocytes reveals extensive proliferation during liver regeneration. Cell Stem Cell, 26, 34-47. (2020)
    https://doi.org/10.1016/j.stem.2019.11.014

  • Matsumoto, Tomonori *, Markus Grompe. "Cells that are the origin of liver regeneration: Polyploid hepatocytes that proliferate while changing ploidy." Experimental Medicine . 38(11), 1884-7. (2020)

This is the first paper to demonstrate that polyploid cells can proliferate sustainably and that plastic changes in ploidy, such as reduction and re-polyploidization, can occur in vivo. Traditionally, polyploidization was believed to lead to the cessation of cell proliferation. In this study, we constructed a mouse model using multicolor reporter mice to visualize and track the proliferation of polyploid cells. By examining the dynamics of polyploid hepatocytes in liver injury, we showed that polyploid hepatocytes can proliferate sustainably in chronically damaged livers and are an important source of regeneration. We also found that proliferating polyploid hepatocytes sometimes undergo multipolar mitosis to produce daughter cells that have undergone ploidy reduction, and that re-polyploidization frequently occurs after this reduction, demonstrating a remarkable plasticity of ploidy. Notably, there have been very few reports of similar phenomena regarding ploidy reduction (depolyploidization), but this study has demonstrated for the first time in vivo that the ploidy of cells can be reduced during cell division of somatic cells.

  • Matsumoto, Tomokuni *, Markus Grompe. "Cells that are the origin of liver regeneration: Polyploid hepatocytes that proliferate while changing ploidy." Experimental Medicine . 38(11), 1884-7. (2020)

1999年以前
Selected papers before 2019

  • Kim SK, Takeda H, Takai A, Matsumoto T, Kakiuchi N, Yokoyama A, Yoshida K, Kaido T, UemotoS, Minamiguchi S, Haga H, Shiraishi Y, Miyano S, Seno H, Ogawa S, Marusawa H*. Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis. J Gastroenterol, 54, 628-640. (2019)

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  • Inuzuka T, Ueda Y, Arasawa S, Takeda H, Matsumoto T, Osaki Y, Uemoto S, Seno H, Marusawa H*. Expansion of viral variants associated with immune escape and impaired virion secretion in patients with HBV reactivation after resolved infection. Sci Rep, 8, 18070. (2018)

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  • Mizuguchi A, Takai A, Shimizu T, Matsumoto T, Kumagai K, Miyamoto S, Seno H, Marusawa H*. Genetic features of multicentric/multifocal intramucosal gastric carcinoma. Int J Cancer, 143, 1923-1934. (2018)

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  • Matsumoto T*, Seno H. Updated Trends in Gallbladder and Other Biliary Tract Cancers Worldwide. Clin Gastroenterol Hepatol. 16, 339-340. (2018)

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  • Matsumoto T, Takai A, Eso Y, Kinoshita K, Manabe T, Seno H, Chiba T, Marusawa H*. Epcam-positive proliferating ductal cells in the inflamed liver give rise to hepatocellular carcinoma in mice. Cancer Res, 77, 6131-6143. (2017)

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  • Matsumoto T, Takahashi K, Inuzuka T, Kim SK, Kurosaki T, Kawakami S, Chiba T, Seno H, Marusawa H*. Activation of TNF-α-AID axis and co-inhibitory signals in coordination with Th1-type immunity in a mouse model recapitulating hepatitis B. Antiviral Res, 139, 138-145. (2017)

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  • Matsumoto T, Shimizu T, Takai A, Marusawa H*. Exploring the mechanisms of gastrointestinal cancer development using deep sequencing analysis. Cancers. 7m 1037-51. (2015)

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  • 松本 知訓*, 猪熊 哲朗. 「胆道癌 特殊な組織型(臨床病理学的特徴) 粘液癌/印環細胞癌」 日本臨床. 73(増刊3), 754-7.(2015)

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  • Matsumoto T, Shimizu T, Nishijima N, Ikeda A, Eso Y, Matsumoto Y, Chiba T, Marusawa H*. Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis. Carcinogenesis, 36, 904-913. (2015)

主な招待講演

Selected invited lectures

  • Development of new cancer treatments through polyploidy research 2024/7/25 Juntendo University Center for Gerontology Moonshot Research Seminar

  • The utility of ploidy as a biomarker and therapeutic target for liver cancer 2024/7/26

  • The 31st Hepatocyte Research Society, 1st Polyploidy Research Society (Mishima, Shizuoka Prefecture, September 25, 2023)
    Elucidation of the mechanism of hepatocarcinogenesis driven by ploidy change

  • The 82nd Annual Meeting of the Japanese Cancer Association (Yokohama, Kanagawa Prefecture, September 21, 2023)
    Exploring therapies targeting cellular senescence dynamics and ploidy alterations associated with cancer progression

  • 2nd Philosophy (Izu City, Shizuoka Prefecture, September 16, 2023)
    Development of new cancer treatments through polyploidy research

  • Liver research seminar in KOBE (Kobe, Hyogo Prefecture, June 4, 2021)
    From basic research to clinical development: Aiming for new breakthroughs

  • Kansai Liver Disease Conference (Osaka City, Osaka Prefecture, October 1, 2020)
    The true identity of liver cells that contain many chromosomes

  • The 42nd Annual Meeting of the Molecular Biology Society of Japan (Fukuoka, Fukuoka, December 4, 2019)
    Robust proliferation and active ploidy alterations of polyploid hepatocytes during liver regeneration

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