1: Tumor-specific inter-endothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness.
Science of the Month - March 2022
J Clin Invest.
2022 Feb 1;e153626. doi: 10.1172/JCI153626.
Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota
The growth of blood vessels into a tumor is necessary for cancer progression and metastasis. For this reason, drugs that stop blood vessel growth (such as VEGF inhibitors) are widely used in clinical practice, but it has been pointed out that their effect on suppressing metastasis is insufficient. In this study, we found that FLRT2, known as a neural guidance factor, is strongly expressed in the blood vessels of human colorectal cancer, especially in advanced cancer, and its expression level is inversely correlated with prognosis. Next, when we transplanted cancer cells into mice with a vessel-specific deletion of the FLRT2 gene, we found a significant reduction in leaky blood vessels (which serve as entry and exit points for cancer metastasis) and a decrease in metastasis to the lungs and liver. Furthermore, we also found that this change in blood vessels (a decrease in leaky vessels) allows blood to be delivered to the deep parts of the cancer, thereby enhancing the effect of immune checkpoint inhibitors. The results of this research are expected to lead to the development of groundbreaking molecular targeted drugs that can efficiently suppress cancer metastasis. The first author, Mr. Ando, has a strong presence and character, but his research skills are exceptionally sharp and refined. We expect great things from him after he returns to the Department of Surgery.
(Yoshiaki Kubota, Class of '79, and Tomofumi Ando, Class of '90, Department of Anatomy)
2: Fast and Durable Intraoperative Near-infrared Imaging of Ovarian Cancer Using Ultrabright Squaraine Fluorophores.
Angew Chem Int Ed Engl.
Fukuda T, Yokomizo S, Casa S, Monaco H, Manganiello S, Wang H, Lv X, Ulumben AD, Yang C, Kang MW, Inoue K, Fukushi M, Sumi T, Wang C, Kang H, Bao K, Henary M, Kashiwagi S, Choi HS.
Ovarian cancer often presents with peritoneal dissemination at the start of treatment, and it is known that prognosis improves if even microscopic lesions smaller than one millimeter can be completely resected. However, surgery still relies on the naked eye of the surgeon, and discovering microscopic cancer in the surgical field is not easy. Fluorescence-guided surgery, which clearly stains cancer, has been gaining attention in recent years as a technology to accurately identify the location of cancer and reduce residual tumors. In this study, we developed a highly bright and stable fluorescent dye with a high affinity for ovarian cancer by modifying the chemical structure and charge of a squaraine dye that fluoresces in the near-infrared region. After intravenous injection, this dye is rapidly taken up into cancer cells via organic cation transporters and accumulates in lysosomes, enabling high-definition detection of microscopic cancer for an extended period of up to 24 hours post-administration in a mouse model of ovarian cancer dissemination. In the future, surgical assistance technologies are expected to become increasingly important, partly due to the rise of robotic surgery. Co-corresponding author Kashiwagi (Class of '76) has a 20-year research career at Massachusetts General Hospital. Through collaborative research with chemistry groups at the same hospital and Georgia State University that design and synthesize fluorescent molecules, he is developing new fluorescent substances specific to cancer and normal tissues.
(Satoru Kashiwagi, Class of '76, Department of Obstetrics and Gynecology)
3: iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders.
Cell Stem Cell.
2022 Feb 3;29(2):189-208. doi: 10.1016
Hideyuki Okano, Satoru Morimoto
In this review, we discussed new directions in research on major neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. We not only covered the discovery of these diseases, their pathophysiology, genetic analysis findings, and iPSC-based disease modeling, drug discovery, and clinical trials, but also delved into emerging areas. These include using polygenic risk scores to stratify sporadic neurodegenerative diseases, predicting pathogenic SNPs in enhancers with deep learning, and validating these predictions by combining iPSC and genome-editing technologies.
(Hideyuki Okano, Class of '62, Department of Physiology)