Annual Report 2024

Laboratory of Integrative Oncology

Yusuke Yamamoto, Mayuko Yamamura, Michiko Ushijima, Hiroki Kataoka

Introduction

 We focus on research regarding non-coding RNAs such as microRNAs, the tumor microenvironment, single-cell/spatial transcriptome analysis, and extracellular vesicles, aiming to elucidate the mechanisms of cancer initiation and progression, as well as to develop diagnostic markers and novel therapeutics.

Research Activities

1) Through spatial transcriptomic and single-cell RNA-seq analyses, we explored the molecules and specific cells involved in the progression of ovarian cancer, lung cancer, breast cancer, and multiple myeloma. In breast cancer, we analyzed the characteristics of lobular carcinoma and examined gene expression profiles across different subtypes. In ovarian cancer, we investigated cell-cell interactions associated with resistance to PARP inhibitors. Furthermore, by downloading single-cell RNA-seq data from public databases and integrating them, we constructed a large-scale dataset to establish a robust and reliable analytical platform. As a result, we revealed that the characteristics of cancer-associated fibroblasts within tumor tissues differ between lung adenocarcinoma and lung squamous cell carcinoma.

2) We performed multi-omics analyses on malignant transformation of teratomas, a rare gynecologic cancer, and identified transcription factors activated in the cancer areas. Using genetic approaches, we inhibited the transcription factor to explore more effective therapeutic agents against the malignant transformation of teratomas in ovary. The efficacy of this strategy was further validated in experiments using patient-derived cells.

3) We explored therapeutic targets for idiopathic pulmonary fibrosis (IPF), an independent risk factor for lung cancer. As a result, we discovered that the PAK2 kinase pathway is activated in fibrotic regions, and demonstrated that its inhibition ameliorates fibrosis both at the cellular level and in a mouse model of pulmonary fibrosis.

Education

 We provided research guidance to PhD and master students and trained young postdoctoral researchers. We had two PhD students from Jikei Medical University, one from Nagoya University, and one from Waseda University, and one master's course student from Keio University and one from the University of Amsterdam.

Future Prospects

 Based on single-cell RNA-seq and spatial transcriptomic analyses, we aim to advance the understanding of tumor microenvironments involved in drug resistance. In addition, we conduct molecular biological analyses to elucidate the intracellular biogenesis of extracellular vesicles secreted by cancer cells. These efforts are directed toward the identification and development of novel therapeutic targets, as well as the establishment of new cancer treatment strategies based on the regulation of extracellular vesicle secretion.

List of papers published in 2024

Journal

1. Yamamoto T, Urabe F, Yoshioka Y, Yamamoto Y, Ochiya T. Protocol for extracellular vesicle secretion-related gene screening via ExoScreen technique. STAR protocols, 6:103569, 2025

2. Yoshida K, Yokoi A, Suzuki H, Tamauchi S, Kitagawa M, Inami E, Nakayama J, Mori Y, Okamoto K, Suzuki Y, Yoshida H, Kato T, Kajiyama H, Yamamoto Y. Single-Nucleus RNA Sequencing and Spatial Transcriptomics for Squamous Cell Carcinoma Arising From Ovarian Mature Teratoma. Cancer science, 116:1339-1351, 2025

3. Harada K, Sakamoto N, Kitaoka T, Nakamura Y, Kondo R, Morisue R, Hashimoto H, Yamamoto Y, Ukai S, Maruyama R, Sakashita S, Kojima M, Tanabe K, Ohdan H, Shitara K, Kinoshita T, Ishii G, Yasui W, Ochiai A, Ishikawa S. PI3 expression predicts recurrence after chemotherapy with DNA-damaging drugs in gastric cancer. The Journal of pathology, 265:472-485, 2025

4. Yoshihara K, Ito K, Kimura T, Yamamoto Y, Urabe F. Single-cell RNA sequencing and spatial transcriptome analysis in bladder cancer: Current status and future perspectives. Bladder cancer (Amsterdam, Netherlands), 11:23523735251322017, 2025

5. Xian W, Wang S, Xie J, Yamamoto Y, Khorrami M, Zhang Y, Montes RC, Desales C, Khorrami M, Mory Z, Hoffman A, Su A, Nguyen C, Davies PJA, Stephan C, Pan S, Wu W, Liu Y, Siegelman J, Waters RE, Ross WA, Song S, Metersky M, Beer DG, Crum CP, Stewart AJ, Vincent M, Russell R, Izard RA, Ho KY, Hung-Sen Lai J, Bachovchin WW, Ajani JA, McKeon FD. Evolution of Esophageal Adenocarcinoma From Precursor Lesion Stem Cells. Gastroenterology, 2025

6. Nakamichi K, Yamamoto Y, Semba K, Nakayama J. Metastatic potentials classified with hypoxia-inducible factor 1 downstream genes in pan-cancer cell lines. Genes to cells : devoted to molecular & cellular mechanisms, 29:169-177, 2024

7. Welsh JA, Goberdhan DCI, O'Driscoll L, Buzas EI, Blenkiron C, Bussolati B, Cai H, Di Vizio D, Driedonks TAP, Erdbrügger U, Falcon-Perez JM, Fu QL, Hill AF, Lenassi M, Lim SK, Mahoney MG, Mohanty S, Möller A, Nieuwland R, Ochiya T, Sahoo S, Torrecilhas AC, Zheng L, Zijlstra A, Abuelreich S, Bagabas R, Bergese P, Bridges EM, Brucale M, Burger D, Carney RP, Cocucci E, Crescitelli R, Hanser E, Harris AL, Haughey NJ, Hendrix A, Ivanov AR, Jovanovic-Talisman T, Kruh-Garcia NA, Ku'ulei-Lyn Faustino V, Kyburz D, Lässer C, Lennon KM, Lötvall J, Maddox AL, Martens-Uzunova ES, Mizenko RR, Newman LA, Ridolfi A, Rohde E, Rojalin T, Rowland A, Saftics A, Sandau US, Saugstad JA, Shekari F, Swift S, Ter-Ovanesyan D, Tosar JP, Useckaite Z, Valle F, Varga Z, van der Pol E, van Herwijnen MJC, Wauben MHM, Wehman AM, Williams S, Zendrini A, Zimmerman AJ, Théry C, Witwer KW. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. Journal of extracellular vesicles, 13:e12404, 2024

8. Kuroiwa Y, Ito K, Nakayama J, Semba K, Yamamoto Y. Analysis of the responsiveness to antiandrogens in multiple breast cancer cell lines. Genes to cells : devoted to molecular & cellular mechanisms, 29:301-315, 2024

9. Nagao Y, Yokoi A, Yoshida K, Kitagawa M, Asano-Inami E, Kato T, Ishikawa M, Yamamoto Y, Kajiyama H. Uterine leiomyosarcoma cell-derived extracellular vesicles induce the formation of cancer-associated fibroblasts. Biochimica et biophysica acta. Molecular basis of disease, 1870:167103, 2024

10. Uehara T, Matsuzaki J, Yoshida H, Ogawa Y, Miura J, Fujimiya H, Yamamoto Y, Kawauchi J, Takizawa S, Yonemori K, Sakamoto H, Kato K, Ishikawa M, Ochiya T. Potential utility of pretreatment serum miRNAs for optimal treatment selection in advanced high-grade serous ovarian cancer. Japanese journal of clinical oncology, 54:917-925, 2024

11. Prieto-Vila M, Yoshioka Y, Kuriyama N, Okamura A, Yamamoto Y, Muranaka A, Ochiya T. Adult cardiomyocytes-derived EVs for the treatment of cardiac fibrosis. Journal of extracellular vesicles, 13:e12461, 2024

12. Yamamoto T, Nakayama J, Urabe F, Ito K, Nishida-Aoki N, Kitagawa M, Yokoi A, Kuroda M, Hattori Y, Yamamoto Y, Ochiya T. Aberrant regulation of serine metabolism drives extracellular vesicle release and cancer progression. Cell reports, 43:114517, 2024

13. Shibata M, Yoshida K, Yokoi A, Suzuki H, Yamamoto Y, Kitagawa M, Asano-Inami E, Yasui Y, Nishiko Y, Yoshihara M, Tamauchi S, Yoshikawa N, Nishino K, Yamamoto E, Niimi K, Kajiyama H. Elucidation of the role of XBP1 in the progression of complete hydatidiform mole to invasive mole through RNA-seq. Gynecologic oncology, 190:189-199, 2024

14. Suzuki K, Yokoi A, Matsuzaki J, Yoshida K, Yamamoto Y, Kato T, Ishikawa M, Ochiya T, Kajiyama H. Circulating serum miRNAs predict response to platinum chemotherapy in high-grade serous ovarian cancer. Cancer medicine, 13:e70251, 2024

15. Nakamichi K, Suzuki H, Yamamoto Y, Semba K, Nakayama J. Nuclear receptor profiling for subtype classification and as prognostic markers in 33 cancer types. Discover oncology, 15:834, 2024