Annual Report 2019
Division of Biomarker Discovery (Tsukiji Campus)
Hiroki Sasaki, Fumiko Chiwaki, Rie Komatsuzaki, Masayuki Komatsu, Masanori Fuse, Moeko Inoue, Takashi Takeda, Tsukasa Fujimoto
The Team and What We Do
The three major research areas of the Department of Translational Oncology were 1) preclinical studies using newly established gastric, esophageal, pancreatic, and ovarian cancer cell lines for deployment of industrial and academia seeds/drugs to the Exploratory Oncology Research & Clinical Trial Center (EPOC), 2) basic research and development of personalized cancer diagnosis and treatment for gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC), and 3) we supported microarray analysis and gene selection for inside and outside researchers as work of the core facility in the Fundamental Innovative Oncology Core Center (FIOC).
Research activities
1. Preclinical Studies Using Newly Established Cell Lines from Common Cancers in Asia
Genome-wide genetic information in about 1,500 cancer cell lines is available on CCLE (Cancer Cell Line Encyclopedia, The Broad Institute of MIT & Harvard); however, among them, only 11 cell lines are derived from diffuse-type GC. Since driver gene mutation frequency in a certain cancer is often less than 5%, the establishment of cell lines from each patient to be analyzed is desired for functional selection of driver gene mutations. The wait is on for the establishment of new GC cell lines, especially from metastatic sites after therapy. Peritoneal metastasis is most frequent in GCs, especially diffuse-type GCs. In 2010-2019, we successfully established over 100 diffuse-type GC cell lines (National Cancer Center Stomach Cancer (NSC) series) from 71 patients, and also established 60 pancreatic and 15 ovarian cancer cell lines, and more. We are conducting omics analyses for gene expression and copy number variation, and hot spot- and genome wide-gene alteration in these cell lines. Moreover, for in vivo preclinical study, their tumorigenicity and histopathological characteristics in the xenograft, such as fibroblast rich-, hypovascular-, and dormant-state, were evaluated. Through collaboration with five pharmaceutical industries, in vitro and in vivo preclinical studies were conducted to deploy clinical trials in our hospitals.
2. Basic Research and Development of Personalized Diagnosis and Treatment for GC and ESCC
The study for GC: GC is one of the leading causes of cancer-related death worldwide.
Histopathologically, GCs can be divided into two major categories: intestinal-type and diffuse-type. Unlike the decreasing incidence of intestinal-type, the prevalence of the diffuse-type is reportedly increasing worldwide. Although therapeutic results for GC have recently improved, the prognosis of patients with advanced diffuse-type GC still remains poor. Peritoneal dissemination is a frequent form of metastasis of diffuse-type GC. The survival rates of patients with peritoneal metastasis (P1) at 3 and 5 years are only 9.8% and 0%, respectively. For improving immunotherapy, we performed cell surface marker analyses by multicolor FCM (flow cytometry) and gene expression analysis using cells derived from the ascites of gastric and ovarian cancer patients. We also developed an ex vivo immune-response evaluation system based on fresh clinical samples and performed prospective omics analysis of patients treated with nivolumab. As a result, we successfully demonstrated that cases with high levels of expression of IFNγ-responsive genes were suggested to be sensitive to nivolumab, and also found the importance of combination therapy of anti-PD-1, -TIGIT, or -TIM-3 antibodies.
The study for ESCC: Definitive chemoradiotherapy (CRT) is a less invasive therapy for ESCC; however, the five-year survival rate of locally advanced ESCC patients was only 37%. Therefore, the prediction of the CRT-responder is awaited. We have successfully identified 2 intrinsic subtypes (M2, and/E) of ESCCs by gene expression profile-based unsupervised clustering of 274 biopsy samples obtained before treatment. For cases treated with CRT, the 5-year survival rate was 24% in subtype M2, whereas it was 74% in subtype E. Furthermore, we found transcriptional pathways activated characteristically in each subtype: subtype E showed a differentiation phenotype, while M2 showed an epithelial-mesenchymal transition phenotype (Tamaoki M, et al., Cancer Sci, 2018, Takashima K, et al., Int. J. Oncology, 2019). To develop an IVD for predicting subtype E with high SIM2 expression, we are collaborating with a pharmaceutical company and ten medical institutes for clinical investigation of 225 ESCC patients with the support of the Japan Agency for Medical Research and Development.
3. Support of Microarray Analysis in the FIOC
In 2019, we supported gene expression and subtyping analyses for inside and outside researchers and provided originally established cancer cell lines to inside and outside researchers and industries under Material Transfer Agreement.
Education
We supported a postdoctoral fellow with their research design, writing a paper, and grant applications, nurtured four assisting scientists, and helped three undergraduate school students with experiments, discussions, and writing reports or papers.
Future prospects
To develop IVD and to deploy new drugs to EPOC, collaboration with pharmaceutical industries will be continued. To facilitate innovative basic research and to create intellectual property, we will make continuous efforts to support inside researchers by providing established cell lines with omics information and microarray analysis.
List of papers published in 2019
Journal
1. Takeda T, Komatsu M, Chiwaki F, Komatsuzaki R, Nakamura K, Tsuji K, Kobayashi Y, Tominaga E,Ono M, Banno K, Aoki D, Sasaki H. Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins. Cell Death Dis. 2019 Nov 20;10(12):876. doi: 10.1038/s41419-019-2117-9. PMID: 31748500 Free PMC ArticleSimilar articles
2. Sasaki M, Chiwaki F, Kuroda T, Komatsu M, Matsusaki K, Kohno T, Sasaki H, Ogiwara H. Efficacy of Glutathione Inhibitors for the Treatment of ARID1A-Deficient Diffuse-Type Gastric Cancers. Biochem Biophys Res Commun. 2020 Feb 5;522(2):342-347. doi: 10.1016/j.bbrc.2019.11.078. Epub 2019 Nov 22. PMID:31761322
3. Takashima K, Fujii S, Komatsuzaki R, Komatsu M, Takahashi M, Kojima T, Daiko H, Minashi K, Chiwaki F, Muto M, Sasaki H, Yano T. CD24 and CK4 are upregulated by SIM2 and become predictive biomarkers for chemoradiotherapy and surgery in esophageal cancer. Int J Oncol. 2020 Mar;56(3):835-847. doi: 10.3892/ijo.2020.4963. Epub 2020 Jan 17.