Annual Report 2023

Laboratory of Integrative Oncology

Yusuke Yamamoto, Mayuko Yamamura

Introduction

 The Laboratory of Integrative Oncology researches to elucidate the diversity of cancer cells and the microenvironment within tumors. As is the case with cancer biology and pathology, cancer cells' nature is complex and diverse. 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 experiences in these areas, we are constantly taking on challenges to develop new therapeutic and diagnostic strategies and elucidate cancer biology.

Research Activities

1) Spatial transcriptome and single-cell RNA-seq analyses were used to search for molecules and cells involved in the progression of lung, breast, and ovarian cancer. In breast cancer, we analyzed the characteristics of lobular carcinoma and the gene expression profiles of different subtypes. In normal lung tissue, we also explored the effects of smoking on each cell type at the single-cell level. Furthermore, we obtained the datasets of lung cancer single-cell RNA-seq from public databases and integrated them to build a more reliable analysis platform. As a result, we found that the characteristics of cancer-associated fibroblasts in lung cancer are different between lung adenocarcinoma and lung squamous cell carcinoma.

2) We performed a multi-omics analysis of the malignant transformation of teratoma (squamous cell carcinoma arising from ovarian mature teratoma), a rare cancer in gynecologic oncology, to identify active transcription factors based on the gene expression profiles. By genetically inhibiting the transcription factors, we searched for more effective therapeutic targets against the malignant transformation of teratoma. We also confirmed the function of these transcription factors using a patient-derived cell culture model.

3) We elucidated the molecular mechanism by which cancer cells specifically secrete extracellular vesicles such as exosomes. We found the relationship between the activated serine synthesis pathway and cancer-specific exosome secretion. In vitro and in vivo experiments revealed that inhibiting exosome secretion suppressed cancer cell metastasis. Furthermore, we showed that exosomes secreted by normal tissues functioned to inhibit cancer cell proliferation and metastasis.

Education

 We provided research guidance to PhD and master students and educated young postdoctoral researchers. We had two PhD students from Jikei Medical University, one from Nagoya University, one from Showa University, and one from Waseda University, and one master course student from Keio University.

Future Prospects

 Our laboratory aims to elucidate the cellular diversity and understand the biological significance in the cancer microenvironment by spatial transcriptome analysis and single-cell RNA-seq. The project aims to identify and analyze the functions of cells in minority populations in the microenvironment. We also try to discover novel therapeutic targets for cell-cell interactions based on the analysis of cancer-specific extracellular vesicles and to develop novel cancer treatment strategies by regulating extracellular vesicle secretion.

List of papers published in 2023

Journal

1. Yamaguchi K, Nakayama J, Yamamoto T, Semba K, Shirota T, Yamamoto Y. Collagen induction of immune cells in the mammary glands during pregnancy. Physiological genomics, 56:128-135, 2024

2. Shiino S, Tokura M, Nakayama J, Yoshida M, Suto A, Yamamoto Y. Investigation of Tumor Heterogeneity Using Integrated Single-Cell RNA Sequence Analysis to Focus on Genes Related to Breast Cancer-, EMT-, CSC-, and Metastasis-Related Markers in Patients with HER2-Positive Breast Cancer. Cells, 12:2286, 2023

3. Ito K, Yamamoto T, Hayashi Y, Sato S, Nakayama J, Urabe F, Shimasaki T, Nakamura E, Matui Y, Fujimoto H, Kimura T, Egawa S, Ochiya T, Yamamoto Y. Osteoblast-derived extracellular vesicles exert osteoblastic and tumor-suppressive functions via SERPINA3 and LCN2 in prostate cancer. Molecular oncology, 17:2147-2167, 2023

4. 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

5. 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

6. 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

7. Yoshida K, Yokoi A, Kitagawa M, Sugiyama M, Yamamoto T, Nakayama J, Yoshida H, Kato T, Kajiyama H, Yamamoto Y. Downregulation of miR‑10b‑5p facilitates the proliferation of uterine leiomyosarcoma cells: A microRNA sequencing‑based approach. Oncology reports, 49:86, 2023

8. Hayashi Y, Nakayama J, Yamamoto M, Maekawa M, Watanabe S, Higashiyama S, Inoue JI, Yamamoto Y, Semba K. Aberrant accumulation of NIK promotes tumor growth by dysregulating translation and post-translational modifications in breast cancer. Cancer cell international, 23:57, 2023

9. Chang X, Tamauchi S, Yoshida K, Yoshihara M, Yokoi A, Shimizu Y, Ikeda Y, Yoshikawa N, Kiyono T, Yamamoto Y, Kajiyama H. Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway. Gynecologic oncology, 173:31-40, 2023

10. Yokoi A, Ukai M, Yasui T, Inokuma Y, Hyeon-Deuk K, Matsuzaki J, Yoshida K, Kitagawa M, Chattrairat K, Iida M, Shimada T, Manabe Y, Chang IY, Asano-Inami E, Koya Y, Nawa A, Nakamura K, Kiyono T, Kato T, Hirakawa A, Yoshioka Y, Ochiya T, Hasegawa T, Baba Y, Yamamoto Y, Kajiyama H. Identifying high-grade serous ovarian carcinoma-specific extracellular vesicles by polyketone-coated nanowires. Science advances, 9:eade6958, 2023

11. Suzuki H, Yokoi A, Uno K, Yoshida K, Kitagawa M, Asano-Inami E, Matsuo S, Nagao Y, Suzuki K, Nakamura K, Yoshihara M, Tamauchi S, Shimizu Y, Ikeda Y, Yoshikawa N, Kajiyama H, Yamamoto Y. Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer. Biochemical and biophysical research communications, 680:211-219, 2023

12. Nakayama J, Yamamoto Y. Cancer-prone Phenotypes and Gene Expression Heterogeneity at Single-cell Resolution in Cigarette-smoking Lungs. Cancer research communications, 3:2280-2291, 2023

13. Yokoi A, Yoshida K, Koga H, Kitagawa M, Nagao Y, Iida M, Kawaguchi S, Zhang M, Nakayama J, Yamamoto Y, Baba Y, Kajiyama H, Yasui T. Spatial exosome analysis using cellulose nanofiber sheets reveals the location heterogeneity of extracellular vesicles. Nature communications, 14:6915, 2023