Annual Report 2018
Department of Translational Oncology
Hiroki Sasaki, Rie Komatsuzaki, Fumiko Chiwaki, Masayuki Komatsu, Kazuaki Yamamoto, Takashi Takeda, Tsukasa Fujimoto, Kenji Takashima
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 derivation 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 diffusetype 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 2010-2018, we successfully established 104 diffuse-type GC cell lines (National Cancer Center Stomach Cancer (NSC) series) from 55 patients, and also established 44 pancreatic and nine 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 derivate 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 diffusetype 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 three and five years are only 9.8% and 0%, respectively. Peritoneal lavage cytology (CY) provides important prognostic information for GC after surgery. CY positive (CY1) is well known as a poor prognostic factor in advanced GC patients. However, the optical therapeutic strategy for patients with CY1 has not yet been established. The 2-, 3-, and five-year survival rates of GC patients with no peritoneal metastasis (P0) but with CY1 are 25.3, 13.8, and 7.8%, respectively. Development of a new therapeutic modality for peritoneal metastasis of GC is very important for improving the outcome of patients with P1/ CY1 or P0/CY1. For personalized medicine, we have developed and improved sensitivity of mini DNA chips containing six markers and three control genes for predicting GC recurrence from peritoneal washings. The CY offers important prognostic information for GC after surgery, but has only a limited sensitivity and the task requires great skill. In 2018, we obtained data from preoperative samples from 316 cases and pre- and post-neoadjuvant chemotherapy samples from 114 cases and compared them to clinicopathological information.
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 CRTresponder is awaited. We have successfully identified five intrinsic subtypes (1a/M1, 2a/I, 3b, 5/M2, and 7/E) of ESCCs by gene expression profile-based unsupervised clustering of 274 biopsy samples obtained before treatment. For cases treated with CRT, the five-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; the subtype E showed a differentiation phenotype, while non-E subtypes including M1 and M2 showed an epithelial-mesenchymal transition phenotype. In 2018, we reported that a transcriptional factor, single-minded family bHLH transcription factor 2 (SIM2) increases CRT sensitivity through differentiation of PDPNpositive malignant basal cells and repression of DNA repair and antioxidant enzymes (FANCD2, XRCC5, and SOD2) by cooperation with ARNT in ESCC (Tamaoki M, et al., Cancer Sci, 2018). To develop an IVD for predicting subtype E with high SIM2 expression, we are collaborating with a pharmaceutical company and ten institutes for clinical investigation of 225 ESCC patients with the support of the Japan Agency for Medical Research and Development, and are preparing the investigator-initiated clinical trial of the immune checkpoint inhibitor for subtype I that shows tumor-specific cytotoxic T-lymphocyte activation signatures by CRT.
3. Support of Microarray Analysis in the FIOC
In 2018, we supported gene expression and subtyping analyses for inside and outside researchers with a total of 592 microarrays, and provided originally established cancer cell lines to four inside and two outside researchers and a company under a 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 derivate new drugs to EPOC, collaboration with pharmaceutical industries will continue. To facilitate innovative basic research and to create intellectual properties, 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 2018
Journal
1. Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, Maruyama A, Makinoshima H, Chiwaki F, Sasaki H, Kato T, Okamoto A, Kohno T. Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers. Cancer Cell, 35:177-190.e8, 2019
2. Tanabe S, Aoyagi K, Yokozaki H, Sasaki H. PTCH1 pathway network model in diffuse-type gastric cancer and epithelial-mesenchymal transition. Journal of Stem Cell Research and Medicine, 3:1-15, 2018
3. Tanabe S, Aoyagi K, Yokozaki H, Sasaki H. Molecular network pathway of ERBB in diffuse-type gastric cancer, mesenchymal stem cells and epithelial-mesenchymal transition. J Clin Epigenet, 4:13, 2018
4. Saeki N, Saito A, Sugaya Y, Amemiya M, Sasaki H. Indirect Down-regulation of Tumor-suppressive let-7 Family MicroRNAs by LMO1 in Neuroblastoma. Cancer Genomics Proteomics, 15:413-420, 2018
5. Tanabe S, Aoyagi K, Yokozak Ki, Sasaki H. Molecular pathway network of EFNA1 in cancer and mesenchymal stem cells. AIMS Cell and Tissue Engineering, 2:58-77, 2018
6. Kamei R, Yoshimura K, Yoshino S, Inoue M, Asao T, Fuse M, Wada S, Kuramasu A, Furuya-Kondo T, Oga A, Iizuka N, Suzuki N, Maeda N, Watanabe Y, Matsukuma S, Iida M, Takeda S, Ueno T, Yamamoto N, Fukagawa T, Katai H, Sasaki H, Hazama S, Oka M, Nagano H. Expression levels of UL16 binding protein 1 and natural killer group 2 member D affect overall survival in patients with gastric cancer following gastrectomy. Oncol Lett, 15:747-754, 2018
7. Tamaoki M, Komatsuzaki R, Komatsu M, Minashi K, Aoyagi K, Nishimura T, Chiwaki F, Hiroki T, Daiko H, Morishita K, Sakai Y, Seno H, Chiba T, Muto M, Yoshida T, Sasaki H. Multiple roles of single-minded 2 in esophageal squamous cell carcinoma and its clinical implications. Cancer Sci, 109:1121-1134, 2018
8. Saeki N, Saito A, Sugaya Y, Amemiya M, Ono H, Komatsuzaki R, Yanagihara K, Sasaki H. Chromatin Immunoprecipitation and DNA Sequencing Identified a LIMS1/ILK Pathway Regulated by LMO1 in Neuroblastoma. Cancer Genomics Proteomics, 15:165- 174, 2018