Annual Report 2022
Department of Translational Oncology
Fumitaka Takeshita, Hiroki Sasaki, Fumiko Chiwaki, Masayuki Komatsu, Megumi Miyagi, Sachika Ueno
Introduction
The three major research areas of the Department of Translational Oncology were: 1) the establishment of cancer cell lines derived from the ascites of patients with cancer for preclinical studies of new cancer therapeutics, 2) studies of the abnormal signaling pathways in cancer cells, and 3) technical support with the generation of cancer model mouse and in vivo imaging for research groups within and outside of the NCC.
Research Activities
1. Establishment of cell lines derived from patients with cancer and development of new cancer treatment methods
Since 2010, we have been attempting to establish new cell lines from the ascites of patients with undifferentiated gastric cancer who frequently experience peritoneal recurrence. As of March 2022, the cumulative number of new cell lines established was 122 from 78 cases (National Cancer Center Stomach Cancer, NSC series). Similarly, 83 cases of pancreatic cancer, 28 cases of ovarian cancer, 2 cases of liposarcoma, and 1 case each of bile duct cancer, gallbladder cancer, mesothelioma, esophagogastric junction cancer, and breast cancer were established successfully. We have conducted joint research with pharmaceutical companies using established strains, and some new drugs have progressed to clinical trials.
2. Development of new diagnostic and therapeutic methods for cervical cancer
We found that although cervical cancers overexpress Aurora kinases A and B, they are less sensitive to inhibitors. Through a series of experiments, we discovered that the phosphorylation of EGFR induced by inhibition of Aurora kinases contributes to the above-mentioned resistance in multiple cancers, including cervical cancer. It was also revealed that this increased phosphorylation occurs by promoting the recycling of EGFR onto the cell membrane. In fact, the combination of Aurora kinases and EGFR inhibitors showed synergistic antitumor effects in both in vitro and in vivo models, suggesting the possibility of a new therapeutic method.
3. Functional elucidation of ARHGAP fusion gene in gastric cancer cells
We discovered an ARHGAP fusion gene that frequently occurs in metastatic gastric cancer cells. In vitro/in vivo functional verification using this fusion gene and cell lines harboring mutant RHOA revealed that the ARHGAP-RhoA signal is involved in E-cadherin-mediated apoptosis. We found that signal inactivation is essential for cancer cell survival.
4. For the purpose of application to the delivery of nucleic acid medicine, we identified some secretory proteins that are taken up by cancer cells.
5. In our laboratory, evaluation of treatments through cancer model studies and imaging for gene medicine molecules such as microRNAs are performed by making good use of this imaging device that detects luminescence and fluorescence from living animals.
6. Cancer model animal production and in vivo imaging analysis support
In response to requests from researchers inside and outside the center, we provided in vivo imaging analysis and support to produce cancer model animals. We provided the following research support:
Creation of cachexia model mice by the transplantation of autologous gastric cancer cell lines
Evaluation of new treatment methods using mouse models of ovarian cancer peritoneal dissemination
Evaluation of new treatment methods using metastatic breast cancer mouse models
Establishment of cell lines derived from bone metastases using lung cancer mouse models
Preparation of pancreatic cancer model mice with orthotopic implantation.
Education
We supported a postdoctoral fellow through research design, writing a paper, and grant applications, and nurtured one trainee who was a vocational school student through experiments, discussion, and writing a report or paper.
Future Prospects
Co-development of new drugs with companies using novel gastric and pancreatic cancer cell lines, etc. will continue. We also plan to continue to develop the application for the delivery of nucleic acid medicine.
List of papers published in 2022
Journal
1. Matsuzaki J, Kato K, Oono K, Tsuchiya N, Sudo K, Shimomura A, Tamura K, Shiino S, Kinoshita T, Daiko H, Wada T, Katai H, Ochiai H, Kanemitsu Y, Takamaru H, Abe S, Saito Y, Boku N, Kondo S, Ueno H, Okusaka T, Shimada K, Ohe Y, Asakura K, Yoshida Y, Watanabe SI, Asano N, Kawai A, Ohno M, Narita Y, Ishikawa M, Kato T, Fujimoto H, Niida S, Sakamoto H, Takizawa S, Akiba T, Okanohara D, Shiraishi K, Kohno T, Takeshita F, Nakagama H, Ota N, Ochiya T. Prediction of tissue-of-origin of early stage cancers using serum miRNomes. JNCI cancer spectrum, 7:pkac080, 2023
2. Kanda M, Serada S, Hiramatsu K, Funauchi M, Obata K, Nakagawa S, Ohkawara T, Murata O, Fujimoto M, Chiwaki F, Sasaki H, Ueda Y, Kimura T, Naka T. Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer. Neoplasia (New York, N.Y.), 35:100853, 2023
3. Komatsu M, Ichikawa H, Chiwaki F, Sakamoto H, Komatsuzaki R, Asaumi M, Tsunoyama K, Fukagawa T, Matsushita H, Boku N, Matsusaki K, Takeshita F, Yoshida T, Sasaki H. ARHGAP-RhoA signaling provokes homotypic adhesion-triggered cell death of metastasized diffuse-type gastric cancer. Oncogene, 41:4779-4794, 2022
4. Komatsu M, Nakamura K, Takeda T, Chiwaki F, Banno K, Aoki D, Takeshita F, Sasaki H. Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling. Oncogene, 41:2326-2339, 2022
5. Urabe F, Matsuzaki J, Takeshita F, Kishida T, Ochiya T, Hirai K. Independent verification of circulating miRNA as diagnostic biomarkers for urothelial carcinoma. Cancer science, 113:3510-3517, 2022
6. Prieto-Vila M, Usuba W, Yoshioka Y, Takeshita F, Yoshiike M, Sasaki H, Yamamoto Y, Kikuchi E, Ochiya T. High-grade bladder cancer cells secrete extracellular vesicles containing miRNA-146a-5p and promotes angiogenesis. Journal of Extracellular Biology, 1:e47, 2022
7. Tsuchiya R, Yoshimatsu Y, Noguchi R, Sin Y, Ono T, Sei A, Takeshita F, Sugaya J, Nakatani F, Yoshida A, Ohtori S, Kawai A, Kondo T. Establishment and characterization of NCC-ssRMS2-C1: a novel patient-derived cell line of spindle cell/sclerosing rhabdomyosarcoma. Human cell, 34:1569-1578, 2021