Annual Report 2022

Laboratory of Integrative Oncology

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) Single cell transcriptomic analysis was used to search for molecules and cells involved in cancer progression. In breast cancer, we investigated the molecular mechanisms underlying the transition of early-stage noninvasive ductal carcinoma in situ (DCIS) to invasive carcinoma. The results showed that DCIS has higher cellular heterogeneity at the level of gene expression and the potential to interact with immune cells, similar to invasive breast cancer. In the analysis of chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lungs, scRNA-seq analysis revealed the presence of inflammatory alveolar epithelial cells that selectively appear in the COPD lungs.

 We also explored the effects of smoking on each cell type of human lungs at the single cell level. We are obtaining the necessary single cell expression analysis data from public databases and integrating human lung scRNA-seq data to build a large dataset to create a more reliable analysis platform.

2) We searched for novel therapeutic targets for rare cancers. In uterine leiomyosarcoma, a gynecological cancer, we identified activated gene pathway based on the gene expression profiles. Using small molecules that inhibit the gene pathways, we found effective therapeutic agents against uterine leiomyosarcoma. Their efficacy was verified in in vivo experiments using xenografting mouse models.

3) We elucidated the secretory mechanism of extracellular vesicle such as exosomes, which were released by cancer cells. Focusing on cancer-specific metabolic pathways, we investigated the molecular mechanism by which cancer cells secrete more exosomes than normal cells. We showed that inhibition of the metabolic pathway suppresses cancer metastasis by decreasing the exosome secretion, and it may be a novel therapeutic strategy. Furthermore, we showed that exosomes secreted by normal tissues function to inhibit cancer cell proliferation and metastasis.

Education

 We provided research guidance to PhD students at cooperating graduate schools and other institutions, and educated young postdoctoral researchers. We had four trainees from Jikei Medical University, one from Nagoya University, one from Showa University, and two from Waseda University

Future Prospects

 Our laboratory aims to discover novel therapeutic targets by focusing on specific cell populations and cell-cell interactions in the cancer microenvironment, develop more accurate cancer diagnostic techniques by detecting cancer specific exosomes in body fluids, and develop novel cancer treatment strategies by inhibiting exosome secretion.

List of papers published in 2022

Journal

1. Yamamoto T, Yamamoto Y, Ochiya T. Extracellular vesicle-mediated immunoregulation in cancer. International journal of hematology, 117:640-646, 2023

2. Watanabe E, Yokoi A, Yoshida K, Sugiyama M, Kitagawa M, Nishino K, Yamamoto E, Niimi K, Yamamoto Y, Kajiyama H. Drug library screening identifies histone deacetylase inhibition as a novel therapeutic strategy for choriocarcinoma. Cancer medicine, 12:4543-4556, 2023

3. Suzuki K, Yokoi A, Yoshida K, Kato T, Ochiya T, Yamamoto Y, Kajiyama H. Preoperative serum microRNAs as potential prognostic biomarkers in ovarian clear cell carcinoma. Journal of gynecologic oncology, 34:e34, 2023

4. Nagao Y, Yokoi A, Yoshida K, Sugiyama M, Watanabe E, Nakamura K, Kitagawa M, Asano-Inami E, Koya Y, Yoshihara M, Tamauchi S, Shimizu Y, Ikeda Y, Yoshikawa N, Kato T, Yamamoto Y, Kajiyama H. Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma. Pharmacological research, 189:106693, 2023

5. Urabe F, Kosaka N, Yamamoto Y, Ito K, Otsuka K, Soekmadji C, Egawa S, Kimura T, Ochiya T. Metastatic prostate cancer-derived extracellular vesicles facilitate osteoclastogenesis by transferring the CDCP1 protein. Journal of extracellular vesicles, 12:e12312, 2023

6. Tokura M, Nakayama J, Prieto-Vila M, Shiino S, Yoshida M, Yamamoto T, Watanabe N, Takayama S, Suzuki Y, Okamoto K, Ochiya T, Kohno T, Yatabe Y, Suto A, Yamamoto Y. Single-Cell Transcriptome Profiling Reveals Intratumoral Heterogeneity and Molecular Features of Ductal Carcinoma In Situ. Cancer research, 82:3236-3248, 2022

7. Zhang Y, Goto Y, Yagishita S, Shinno Y, Mizuno K, Watanabe N, Yamamoto Y, Ota N, Ochiya T, Fujita Y. Machine learning-based exceptional response prediction of nivolumab monotherapy with circulating microRNAs in non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands), 173:107-115, 2022

8. Suzuki K, Yamaguchi T, Kohda M, Tanaka M, Takemura H, Wakita M, Tabe Y, Kato S, Nasu M, Hashimoto T, Mine S, Serizawa N, Tomishima K, Nagahara A, Matsuda T, Yamaji T, Tsugane S, Saito Y, Daiko H, Yoshikawa T, Kato K, Okusaka T, Ochiya T, Yamamoto Y, Yotsui S, Yamamoto T, Yamasaki T, Miyata H, Yasui M, Omori T, Ohkawa K, Ikezawa K, Nakabori T, Sugimoto N, Kudo T, Yoshida K, Ohue M, Nishizawa T. Establishment of preanalytical conditions for microRNA profile analysis of clinical plasma samples. PloS one, 17:e0278927, 2022

9. Suzuki K, Igata H, Abe M, Yamamoto Y. Multiple cancer type classification by small RNA expression profiles with plasma samples from multiple facilities. Cancer science, 113:2144-2166, 2022

10. Urabe F, Matsuzaki J, Ito K, Takamori H, Tsuzuki S, Miki J, Kimura T, Egawa S, Nakamura E, Matsui Y, Fujimoto H, Yamamoto Y, Ochiya T. Serum microRNA as liquid biopsy biomarker for the prediction of oncological outcomes in patients with bladder cancer. International journal of urology, 29:968-976, 2022

11. Yoshida K, Yokoi A, Yamamoto T, Hayashi Y, Nakayama J, Yokoi T, Yoshida H, Kato T, Kajiyama H, Yamamoto Y. Aberrant Activation of Cell-Cycle-Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma. Clinical cancer research, 28:2147-2159, 2022

12. Nakayama J, Matsunaga H, Arikawa K, Yoda T, Hosokawa M, Takeyama H, Yamamoto Y, Semba K. Identification of two cancer stem cell-like populations in triple-negative breast cancer xenografts. Disease models & mechanisms, 15:dmm049538, 2022

13. Watanabe N, Fujita Y, Nakayama J, Mori Y, Kadota T, Hayashi Y, Shimomura I, Ohtsuka T, Okamoto K, Araya J, Kuwano K, Yamamoto Y. Anomalous Epithelial Variations and Ectopic Inflammatory Response in Chronic Obstructive Pulmonary Disease. American journal of respiratory cell and molecular biology, 67:708-719, 2022

14. Urabe F, Yamamoto Y, Kimura T. miRNAs in prostate cancer: Intercellular and extracellular communications. International journal of urology, 29:1429-1438, 2022

15. 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. J of Extracellular Bio, 1:e47, 2022