Research

Introduction

In the field of tumor biology, we focus on epigenetic abnormalities, particularly those related to the dysregulation of genes implicated in disease onset. Our research aims to conduct fundamental studies on these abnormalities and develop diagnostic and therapeutic approaches targeting epigenetic abnormalities. For instance, epigenetic abnormalities induce carcinogenesis through dysregulation of cell differentiation and proliferation control, leading to diverse changes in the characteristics of cancer cells in response to the surrounding environment, ultimately acquiring malignant traits. Deepening our understanding of epigenetic abnormalities serves as a clue to effective cancer therapy. We believe that by aiming to normalize or control epigenetic abnormalities, we can develop new treatment modalities. We engage in organic collaborative research with researchers domestically and internationally, attempting to refine and apply practical applications by sharing our findings with clinical departments.

Goals

Our goal is to contribute to next-generation cancer medicine through the practice of basic medical research on cancer. In developing strategies for cancer treatment, establishing a molecular understanding and diagnosis and treatment based on its molecular basis are essential for the development of effective cancer therapy.

Epigenetic abnormalities, which we are researching, are present in almost all cancer cells, making them highly useful as diagnostic markers. Particularly, DNA methylation within the epigenome is a stable chemical modification, and abnormalities specific to cancer cells are detected in a wide range of human genes, making it an excellent diagnostic marker. We are developing cancer diagnostic markers utilizing this characteristic and also developing new detection methods that can sensitively and conveniently analyze minute DNA methylation abnormalities. On the other hand, therapeutics targeting epigenetic abnormalities are expected to be a new class of cancer therapeutics with different mechanisms of action from conventional molecular targeted drugs. Indeed, the development of epigenetic therapeutics is currently accelerating

worldwide. In our laboratory, we are extensively studying cancer epigenetics and actively attempting to develop therapeutics through collaborative research with external researchers.

We believe that if we can capture cancer-specific epigenetic abnormalities "early" and "reliably" for diagnosis and control the Achilles' heel of cancer with epigenetic therapeutics, we can deploy new cancer treatment strategies.

Introduction to Research Content

Cancer Cells and Epigenetics

The cells constituting our body adeptly utilize (read) genes (blueprints) as a single fertilized egg divides, eventually giving rise to cells that form the skin or bones. This mechanism of determining gene usage is termed "epigenetics." The concept of epigenetics was proposed by Dr. Waddington in 1942, predating the DNA double helix model by Drs. Watson and Crick (1953), as "causal mechanisms by which the genes of the genotype bring about phenotypic effects." Due to the lack of a perfect Japanese translation for epigenetics, it is mostly represented in katakana. In China, it is described as "表現遺伝学" (expression genetics), which might be more understandable.

Factors regulating chromatin structure, histone modifications, DNA methylation, non-coding RNAs, and other epigenetic elements are collectively referred to as the epigenome and are typically tightly controlled. However, exposure to aging or environmental substances can lead to chemical alterations in these regulatory mechanisms (epigenetic abnormalities). Furthermore, it is believed that accumulated epigenetic abnormalities contribute to cellular transformation into cancer. Indeed, upon examining cancer cells, epigenetic abnormalities are detected in nearly all cases, influencing their characteristics from the early stages to advanced cancer.

Introduction to Research Content

The detection of epigenetic abnormalities in almost all cancer cells suggests its potential application in early cancer diagnosis. Moreover, unlike "genetic mutations," it's understood that epigenetic abnormalities are highly reversible with drugs, thus targeting epigenetics abnormalities in cancer cells could lead to novel cancer treatments.

We meticulously analyze the epigenetic abnormalities in cancer cells using microarrays and high-speed sequencers, aiming to contribute to cancer diagnosis and develop new cancer treatments by normalizing abnormal epigenetics. Through such efforts, we aim not only to elucidate the mechanisms of carcinogenesis but also to pursue cancer research aimed at practical application in cancer care.

Since the fiscal year 2011, we have been participating in the Ministry of Education, Culture, Sports, Science, and Technology's "Next-generation Cancer Research Seed Strategy Development Program" as the team leader of the Cancer Epigenome Team, striving to realize innovative cancer medicine through our research. (http://p-direct.mext.go.jp/program/group01/team04.html)

Epigenetics Research Targeting Cancer Diagnosis and Treatment

Exposure to carcinogens or environmental substances can lead to abnormal DNA methylation. In such cases, genes that would normally suppress cancer may lose their function due to abnormal DNA methylation, leading to carcinogenesis. This DNA methylation is implicated in the characteristics of cancer from its initiation to the stage of infiltration and metastasis. Therefore, if abnormal DNA methylation can be detected in blood, it is believed that cancer diagnosis becomes feasible. In the Western world, a gene called Septin9 has been approved as a blood diagnostic DNA methylation marker for colorectal cancer and is actively used in practice. We have conducted comprehensive analyses of DNA methylation in various types of malignant tumors, including colorectal cancer, liver cancer, pancreatic cancer, lung cancer, and malignant pleural mesothelioma. Through this work, we have identified characteristic DNA methylation patterns specific to each tumor type. Currently, based on these findings, we are striving to establish new blood diagnostic methods that enable early cancer detection. Additionally, we are collaborating with the engineering department to develop innovative detection methods capable of detecting minute amounts of DNA methylation in blood.

Elucidating the Mechanism of DNA Methylation Induction by Chronic Inflammation

The onset of cancer is believed to be deeply influenced by environmental factors. For instance, carcinogenic substances with genotoxic effects induce gene mutations through genomic damage. Interestingly, recent large-scale gene analyses have revealed that while cancer cells indeed harbor gene mutations involved in proliferation and survival, as predicted, there is an unexpected accumulation of mutations in epigenetic control genes. From these findings, it is considered that epigenetic abnormalities induced by genomic abnormalities are also important in carcinogenesis. On the other hand, chronic inflammation due to infectious diseases can also be a cause of cancer. In Japan, it is known that many cases of hepatocellular carcinoma primarily arise from chronic hepatitis caused by hepatitis B and C viruses (HBV, HCV). Laboratories both domestically and internationally, including ours, have reported the accumulation of epigenetic abnormalities genome-wide in the state of chronic hepatitis, suggesting the formation of a "precancerous state." However, the mechanism by which HBV and HCV induce epigenetic abnormalities after infection has not been analyzed in vivo (within living organisms). In our laboratory, we conducted analyses using human liver cell-chimeric mice susceptible to HBV and HCV infection. As a result, we found that after viral infection, the innate immune system centered around natural killer (NK) cells induced DNA methylation abnormalities in liver cells through the production of IFNγ. DNA methylation abnormalities accumulated significantly with the progression of infection duration, particularly showing pronounced acceleration of age-related DNA methylation abnormalities. Induction of DNA methylation abnormalities was suppressed by inhibiting the function of NK cells using inactivated antibodies. Thus, epigenetic abnormalities are induced not only by genomic abnormalities but also by various causes (in this study, chronic inflammation after viral infection), and are likely to be involved in carcinogenesis through abnormalities in gene regulation. Moving forward, we aim to explore new possibilities for the development of control methods by elucidating the molecular mechanisms of epigenetics involved in carcinogenesis.

Research on Non-Coding RNAs Involved in the Differentiation Control of Brain Tumor Stem Cells

Solid tumors generally exhibit tumor heterogeneity, consisting of various cells with different phenotypes, which remains a significant challenge in cancer treatment as it complicates achieving a cure with current therapies. We are conducting research on the mechanisms underlying tissue heterogeneity formation.

Within tumors, there exists a population of cells with stem cell-like properties, capable of self-renewal and differentiation into cells with different phenotypes. This subgroup, known as cancer stem cells, is proposed to compose cancer tissues along with differentiated cancer cells. We hypothesize that the presence of cancer stem cells and epigenetic cellular regulatory mechanisms are involved in the background of tissue heterogeneity formation, and we are conducting research to explore this.

Control of gene expression by non-coding RNAs within the epigenome (microRNAs, miRNAs, long non-coding RNAs, lncRNAs) has been found to be deeply involved in various biological processes such as cell differentiation and proliferation. Using glioblastoma-derived cancer stem cells (Glioma stem-like cells, GSCs) as a model, we are investigating the expression changes of non-coding RNAs (miRNAs, lncRNAs) during GSC differentiation. Our goal is to elucidate the epigenetic regulatory mechanisms involved in GSC differentiation control. Currently, we have identified multiple non-coding RNAs involved in GSC regulation.

Analysis of Epigenetic Aberrations Involved in the Onset and Progression of Gliomas

Among gliomas, glioblastoma, a type of glioma, is the most frequently occurring malignant brain tumor, and it remains one of the most challenging tumors to cure. Despite the combination of chemotherapy and radiation therapy following surgery, the median survival period is approximately 15 months, highlighting the urgent need for novel treatment strategies.

Recent large-scale genetic analyses have revealed that glioblastomas can be categorized into primary glioblastomas and secondary glioblastomas, which evolve from low-grade gliomas in multiple stages, each with distinct genetic backgrounds. Thus, within glioblastomas, it is speculated that there exists a mixture of tumor groups with significantly different molecular mechanisms of oncogenesis, particularly evident in low-grade gliomas and secondary glioblastomas, where mutations in epigenetic-related genes are frequently observed.

Cancer is a disease caused by genomic and epigenomic abnormalities, and it is highly likely that the accumulation of epigenetic aberrations also contributes to the oncogenesis of brain tumors. Therefore, we aim to identify epigenetic abnormalities involved in the onset and progression of brain tumors using a spontaneous mouse model of brain tumor formation. Additionally, in collaboration with the Department of Neurosurgery at Nagoya University, we aim to develop novel treatment strategies for brain tumors targeting their molecular mechanisms.