1: Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent
Science of the Month - October 2018
Nature Medicine
20 August 2018, doi: 10.1038/s41591-018-0140-5.
Koki Fujimori, Mitsuru Ishikawa, Asako Otomo, Naoki Atsuta, Ryoichi Nakamura, Tetsuya Akiyama, Shinji Hadano, Masashi Aoki, Hideyuki Saya, Gen Sobue & Hideyuki Okano
Our research group, led by Koki Fujimori, conducted research on the pathophysiology of ALS and drug discovery using iPS cell technology. Focusing on motor neurons derived from iPS cells of patients with non-SOD1 familial ALS with mutations in the FUS or TDP43 genes, which code for RNA-binding proteins, we screened a library of 1,232 existing drugs using drug repositioning to find compounds that suppress ALS-related phenotypes, and we identified nine drugs. Among these, ropinirole hydrochloride (ROPI) showed the greatest therapeutic effect. As a D2 receptor agonist, it is a drug widely used worldwide for the treatment of Parkinson's disease and is also covered by insurance in Japan. On the other hand, it was shown that only a part of the anti-ALS activity of ROPI is mediated by D2R, and that it is due to the suppression of ROS production and the enhancement of mitochondrial activity. Furthermore, we analyzed iPS cell-derived motor neurons from 32 cases of sporadic ALS and found that ROPI had an inhibitory effect on motor neuron degeneration in vitro not only in non-SOD1 familial ALS but also in about 70% of sporadic ALS cases. In motor neurons, it was predicted that the group exhibiting FUS or TDP-43 accumulation phenotypes would be the ROPI responders, while the group without accumulation would be the non-responders. However, we believe it is necessary to discover more reliable biomarkers to more accurately predict and determine the therapeutic effect.
(Hideyuki Okano, Class of 1962, Department of Physiology)
2: Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis
CELL
174 (4):856-+; 10.1016/j.cell.2018.07.027 AUG 9 2018
Nanki Kosaku, Toshimitsu Kohta, Takano Ai, Fujii Masayuki,Shimokawa Mariko, Ohta Yuki, Matano Mami, Seino Takashi, NishikoriShingo, Ishikawa Keiko, Kawasaki Kenta, Togasaki Kazuhiro, TakahashiSirirat, Sukawa Yasutaka, Ishida Hiroki, Sugimoto Shinya, KawakuboHirofumi, Kim Jihoon, Kitagawa Yuko, Sekine Shigeki, Koo Bon-Kyoung,Kanai Takanori, Sato Toshiro
Advances in sequencing technology are revealing the full picture of genomic abnormalities in cancer. However, how genetic mutations lead to cancer malignancy remains unclear, and there has been a long-awaited need for technology to investigate the biological properties of patients' tumors. With the significant cooperation of doctors from the gastroenterology cluster, including general and gastroenterological surgery, the Cancer Center, the Endoscopy Center, and the Center for Preventive Medicine, our laboratory has succeeded in culturing gastric cancer from 35 patients as organoids. Through this research, we have identified a new growth control mechanism for gastric cancer. Normal gastric epithelium requires a growth factor called R-spondin, but we found that about 40% of gastric cancer cells can proliferate without it. Interestingly, these R-spondin-independent gastric cancers have double mutations in E-cadherin and p53, and we demonstrated that by introducing these double mutations into normal gastric epithelium, we could reproduce R-spondin-independent proliferation. R-spondin-independent gastric cancer is often found in scirrhous gastric cancer and shows a high dependence on a growth factor called Wnt, raising expectations for the development of new therapeutic methods in the future.
(Toshiro Sato, Class of 1976, and Kosaku Nanki, Class of 1986, Gastroenterology, Department of Internal Medicine)