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Research

Tumor tissue is a complex system composed of tumor cells and multiple types of stromal cells. It is important for the understanding of developmental mechanisms of the disease to reveal the cell-cell interactions and interferences. Our purpose is to understand the dynamic multicellular interactions in such a complicated biological system by measuring a large amount of data at the genomic level, which leads to the identifications of therapeutic targets and biomarkers.

Furthermore, we also investigate the genomic approach for analyzing various intractable diseases. We are trying to reveal the molecular mechanism of such diseases by comprehensively genomic analysis of clinical samples.

Genomic Approach for the Cancer-Stromal Interaction

In the department of genomic pathology, we have developed a new method to analyze a wide range of cancer-stromal interactions in tumor tissues which are composed of various types of cells.
We are exploring new targets of drugs for cell-to-cell interactions by investigating a global view of the tumor-stroma interactome. Furthermore, by using a direct xenograft model (PDX: Patient Derived Xenograft), we are investigating the interactome analysis of multiple clinical tumors in order to make it possible to clarify the cell-cell interactome in primary human tumors.

Functional Genomic Screening

We are developing a method for the comprehensive characterizations of fibroblast clones in the tumor stroma by combining a whole-genomic shRNA library and massively-parallel sequencing. We are comprehensively revealing what kinds of gene knockdown in fibroblasts cause what kinds of responses in tumor tissues in vivo. We are exploring new druggable molecules targeting the disruption of the tumor stroma by elucidating molecular mechanisms of tumor stroma formation.

Genomics Analysis for Clinical Disease Tissues

We have been investigating various clinical disease samples such as scirrhous carcinoma by genomics approaches. By utilizing massively-parallel sequencing, we are obtaining comprehensive data of transcriptome and whole exome sequencing of clinical tissue samples and trying to elucidate the pathogenic mechanism of the diseases defined by genomics aspects.

Analysis of Antigen Receptor Repertoire in Tumor Infiltrating Lymphocytes

Tumor infiltrating lymphocytes (TILs) seem to play important roles in cancer immunity, as suggested by the finding that the amount of TILs correlates with prognosis in various cancer. However, their functions have remained largely unknown.
In the department of genomic pathology, we try to uncover the functions of TILs in cancer environment by analyzing their antigen receptor sequences using massively-parallel sequencing technology (Fig. 2). Our main focus is on diffuse gastric cancer, which is characterized by very poor prognosis and few actionable driver mutations for molecular targeting therapy. Due to its low mutation load, diffuse gastric cancer is expected to respond poorly to immune checkpoint blockade such as anti-PD-1 therapy. Our analysis provides a promising approach to define TIL characteristics and may lead to the development of improved cancer immunotherapy.

In Silico Design of Chemical Compounds and Simulation of Activation

By using the structures of target proteins, we are designing a screening strategy of active compounds in silico. And we are developing new simulation methods to understand and to optimize the working mechanism by using molecular dynamics.