Laboratory of Oncogenomics

Dr. Osamu Shimozato obtained his Ph.D. in Medical Science at Juntendo University Graduate School of Medical Science and carried out his postdoctoral research at the National Cancer Institute at Frederick under Dr. Howard Young (1999~2001). Through these research experiences, he studied the regulation and characterization of cytokines and cell surface proteins that regulate T-cell-mediated immune responses. He was assigned to the Chiba Cancer Center Research Institute (CCCRI) in 2001. He has been in his current position (laboratory chief) since 2017.

Cancer is the leading cause of death in Japan, and the development of treatment methods is an urgent issue. Cancer patients are treated primarily with surgery, radiation therapy, and chemotherapy; however, it is difficult to completely cure cancer without surgery. The reason for this is that patients with advanced cancer who are not able to undergo surgery often experience recurrence several years after treatment. As an ancient Chinese philosopher, Sun Tzu said, “If you know him and know yourself, you won’t be in danger of a hundred battles,” I believe that a good understanding of cancer at the molecular level is necessary to achieve a radial cure for cancer. In the 2000s, the “cancer stem cells” hypothesis was proposed. This hypothesis strongly suggests that certain types of cancer cells, so-called cancer stem cells, may be the source of cancer development and recurrence, just as “tissue stem cells” are the source of normal tissues and are resistant to various types of stresses. Therefore, I am conducting research on cancer stem cells, including functional analysis of CD133, a cancer stem cell marker, and molecular mechanisms of drug resistance acquisition through epigenetic gene regulation.

The history of cancer research has tightly linked to genetic analysis. The “Research Center for Functional Genomics” was established in 2001 in collaboration with Hisamitsu Pharmaceutical Co., Inc., to conduct joint research using advanced gene analysis technologies, such as microarray and massively parallel high-throughput sequencing. Dr. Ohira, a former member of the CCCRI (currently affiliated with the Research Institute for Clinical Oncology, Saitama Cancer Center), was the first Chief of the laboratory of Oncogenomics, where she established a novel diagnostic system that accurately predicts the prognosis of neuroblastoma patients. Based on the results of this laboratory, I intend to conduct further basic research to establish appropriate and reliable strategies for the diagnosis and treatment of cancer, ultimately aiming for the eradication of the disease.

Members

Laboratory Head	Osamu Shimozato

Projects

Elucidation of property of cancer stem cells to develop a novel strategy of diagnosis and anti-cancer drug

Chemotherapy and radiotherapy cure many cancer patients, but some patients develop recurrent cancer several years after treatment. It is considered that cancer cells within recurrent cancer tissues have acquired strong resistance to treatment through various strategies. Recently, it has been postulated that a certain number of specific cancer cells may exist in cancer tissues that are highly resistant to treatment. Such specific cancer cells are referred to as “cancer stem cells”, and have become a trend in the field of cancer research. In our laboratory, we are working on developing reliable diagnosis strategies and novel anti-cancer drugs by clarifying the property of cancer stem cells and elucidating the molecular mechanism by which cancer stem cells acquire resistance to therapy.

1. Functional analysis of cancer stem cell marker CD133

CD133 has been discovered as one of the membrane proteins that is expressed specifically in blood and stem cells of normal tissues. Since CD133-positive cancer cells have been shown to have a strong oncogenic ability and resistance to therapy, it is suggestive that CD133 might be a molecular marker to identify cancer stem cells. We have participated in functional analysis of CD133 by taking advantage of colon cancer-derived cells and found that CD133 plays a vital role in the regulation of oncogenic potential and resistance against therapy of cancer stem cells (Fig. 1).

2. Elucidation of molecular mechanisms behind epigenome-mediated drug resistance

It is well known that numerous proteins with various functions are involved in the acquisition of resistance against the therapy of cancer cells. For example, it is well documented that molecular pumps which excrete drugs from cells and enzymes which neutralize drugs are highly expressed in therapy-resistant cancer cells. In general, the information for protein is encoded in DNA, transferred to mRNA, and then proteins are generated based on the mRNA. The transcription process is regulated by DNA sequences of promoter regions recognized by transcription factors or by chemical modification of DNA and its adjacent proteins (Fig. 2). The latter mechanism is distinct from that dependent on the genetic information encoded in DNA, and is therefore called “regulation by epigenome,” and has attracted much attention. Among them, our laboratory is focusing on the enzymatic activity involved in the methylation of histone H3 at Lys-4 (Fig. 2).

3. Development of a reliable inspection system for blood sample

Once cells within a living organism have been destroyed for any reason, DNA fragments termed cell-free DNA (cfDNA) are released into the bloodstream. In cancer patients, mutated cfDNA is released from cancer cells. This cfDNA derived from cancer cells is referred to as circulating tumor DNA (ctDNA) and has been applied to gene panel testing, although certain criteria should be satisfied. Genetic information reflects the original features of cancer cells, and thus enables highly accurate cancer screening. Since the amount of ctDNA present in blood is extremely small, some improvements have to be required to accurately detect this ctDNA. We are working on developing a technique to concentrate ctDNA using an organic compound with sequence-specific DNA-binding ability to increase the detection sensitivity to mutated DNA (Fig. 3). Based on this strategy, we are promoting a project to develop a novel detection system for driver genes and metabolic enzymes responsible for carcinogenesis。

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