Annual Report 2021
Integrative Oncology Unit
Yusuke Yamamoto
Introduction
The Laboratory of Integrative Oncology conducts research aimed at elucidating the diversity of cancer cells and the microenvironment within tumors. As is the case with cancer biology and pathology, the nature of cancer cells is complex and full of diversity. To understand these characteristics of cancer cells, it is essential to take a multifaceted approach, which requires technological innovation and imaginative research ideas. Specifically, we use bio-imaging, single cell expression analysis, screening with compound libraries, and tissue stem cell culture techniques. Based on our accumulated experience in these areas, we are constantly taking on challenges to develop new therapeutic and diagnostic strategies as well as elucidate cancer biology.
Research activities
1) Our research group investigated the secretion mechanism of extracellular vesicles, such as exosomes and microvesicles, released by cancer cells and normal cells. Furthermore, we demonstrated that suppressing extracellular vesicles can inhibit cancer progression and metastasis, which may be a novel therapeutic strategy. In addition, we identified specific miRNAs and proteins abundantly contained in extracellular vesicles in the blood of cancer patients and developed a novel biomarker to predict prognosis as well as achieve early detection of cancers, based on serum miRNA profiling. We also showed that extracellular vesicles secreted by normal cells functioned to inhibit the growth and metastasis of cancer cells.
2) We searched for novel therapeutic agents against cancer cells with specific genetic mutations and rare types of cancers. For this purpose, drug screening was conducted and several candidate compounds were identified. Uterine leiomyosarcoma and breast cancer were the target tissues, and it was shown that the drugs identified in the screening were significantly effective against these kinds of cancer cells. Furthermore, we elucidated the molecular mechanisms of the anti-tumor effects of those drugs on cancer cells through in vitro and in vivo approaches.
3) Single cell RNA sequencing was performed to examine gene expression profiles at single cell resolution and was used to search for molecules and cells involved in the progression of lung and breast cancer. In breast cancer, we elucidated the molecular mechanism by which non-invasive ductal carcinoma of the breast (DCIS, ductal carcinoma in situ) transforms into invasive carcinoma and also showed intratumoral heterogeneity in DCIS. In lung cancer, we explored the effects of smoking on each cell type at the single cell level. Furthermore, we obtained a large amount of single cell RNA sequencing data from public databases and integrated them to construct a large-scale data set for building a more reliable analysis platform. We are also conducting single cell expression analysis for inflammatory diseases such as chronic obstructive pulmonary disease (COPD). We are seeking to understand the molecular and cellular basis of precancerous lesions, to analyze the process of tumorigenesis progression from normal tissues.
Education
We provided research guidance to PhD students at cooperating graduate schools and other institutions, and educated young postdoctoral researchers. We had three trainees from Jikei Medical University, one from Showa University, one from Keio University, two from Waseda University, and one from Nagasaki University.
Future Prospects
This research unit aims to contribute to the development of cancer treatment and diagnostic methods. We will establish more accurate cancer diagnostic techniques based on the purification of extracellular vesicles. Also, we will actively introduce novel analytical techniques such as single cell expression analysis, aiming to elucidate the nature of cancer and search for novel therapeutic targets.
List of papers published in 2021
Journal
1. Yoshida K, Yokoi A, Matsuzaki J, Kato T, Ochiya T, Kajiyama H, Yamamoto Y. Extracellular microRNA profile for prognostic prediction in patients with high-grade serous ovarian carcinoma. Cancer Science, 112(12):4977-4986. (2021) PMID: 34618992
2. Shimomura I, Watanabe N, Yamamoto T, Kumazaki M, Tada Y, Tatsumi K, Ochiya T & Yamamoto Y. Verteporfin Selectively Targets KRAS-driven Lung Tumorigenesis via Unresolved ER Stress. JCI Insight, 6(7): e137876. (2021) PMID: 33830081
3. Yoshida K, Yokoi A, Yamamoto Y, Kajiyama H. “ChrXq27.3 miRNA cluster functions in cancer development.” J Exp Clin Cancer Res. 40(1):112. (2021) PMID: 33766100
4. Watase C, Shiino S, Shimoi T, Noguchi E, Kaneda T, Yamamoto Y, Yonemori K, Takayama S, Suto A. “Breast Cancer Brain Metastasis-Overview of Disease State, Treatment Options and Future Perspectives.” Cancers (Basel). 13(5), 1078. (2021) PMID: 33802424
5. Nakayama J, Han Y, Kuroiwa Y, Azuma K, Yamamoto Y, Semba K. “The in vivo selection method in breast cancer metastasis.” IJMS, 22(4): 1886. (2021) PMID: 33672831
6. Yoshida K, Yamamoto Y, Ochiya T. “miRNA signaling networks in cancer stem cells.” Regen Ther. 17:1-7. (2021) PMID: 33598508
7. Zhou Y, Yamamoto Y, Takeshita F, Yamamoto T, Xiao Z, Ochiya T. “Delivery of miR-424-5p via Extracellular Vesicles Promotes the Apoptosis of MDA-MB-231 TNBC Cells in the Tumor Microenvironment.” Int J Mol Sci. 22(2):844. (2021) PMID: 33467725
8. Hashimoto K, Inada M, Yamamoto Y & Ochiya T. Preliminary evaluation of miR-1307-3p in human serum for detection of 13 types of solid cancer using microRNA chip. Heliyon, 7(9):e07919. (2021) PMID: 34541347
9. Harada K, Sakamoto N, Ukai S, Yamamoto Y, Thang PQ, Taniyama D, Honma R, Maruyama R, Takashima T, Ota H, Takemoto Y, Tanabe K, Ohdan H, Yasui W. Establishment of oxaliplatin-resistant gastric cancer organoids: importance of myoferlin in the acquisition of oxaliplatin resistance. Gastric Cancer, 24(6):1264-1277. (2021) PMID: 34272617
10. Kadota T, Fujita Y, Araya J, Watanabe N, Fujimoto S, Kawamoto H, Minagawa S, Hara H, Otsuka T, Yamamoto Y, Kuwano K & Ochiya T. Human bronchial epithelial cell-derived extracellular vesicle therapy for pulmonary fibrosis via inhibition of TGF-β-WNT crosstalk. JEV, 10(10):e12124. (2021) PMID: 34377373
11. Yano K, Takahashi RU, Shiotani B, Abe J, Shidooka T, Sudo Y, Yamamoto Y, Kan S, Sakagami H, Tahara H. PRPF19 regulates p53-dependent cellular senescence by modulating alternative splicing of MDM4 mRNA. JBC, 297(1):100882. (2021) PMID: 34144037
12. Urabe F, Kimura T, Ito K, Yamamoto Y, Tsuzuki S, Miki J, Ochiya T, Egawa S. Urinary extracellular vesicles: a rising star in bladder cancer management. Transl Androl Urol. 10(4):1878-1889. (2021) PMID: 33968676
13. Kohama I, Asano N, Matsuzakia J, Yamamoto T, Yamamoto Y, Takahashi RU, Kobayashi E, Kawai A, Takizawa S, Sakamoto H, Chikuda H & Ochiya T. Comprehensive miRNA profiling between serum and tissue in Dedifferentiated liposarcoma. Oncology letters, 22(2):623. (2021) PMID: 34285721