Annual Report 2018
Division of Molecular and Cellular Medicine
Takahiro Ochiya, Yusuke Yamamoto, Takeshi Katsuda, Yusuke Yoshioka, Ayako Inoue, Kana Kurosaki, Mayuko Yamamura, Nobuyoshi Kosaka, Luc Gailhouste, Ai Hironaka, Takumi Sonoda, Hiroko Tadokoro, Juntaro Matsuzaki, Marta Prieto Vila, Anna Sanchez Calle, Akiko Kogure, Yutaka Naito, Tomomi Imamura, Naomi Nomura, Teruko Yamaguchi, Kazumi Nagao, Megumi Miyagi, Yurika Sawa, Hikaru Sonoda, Satoko Takizawa, Maki Abe, Kurataka Otsuka, Tsukasa Kadota, Junpei Kawauchi, Fumihiko Urabe, Yumi Kawamura, Wataru Usuba, Iwao Shimomura, Isaku Kohama, Tomofumi Yamamoto, Tomoko Yamaguchi, Ryou-u Takahashi, Minami Kumazaki, Makiko Ichikawa, Lee Chuen Liew, Yueyuan Zhou
Introduction
The focus of the Division of Molecular and Cellular Medicine lies in the development of novel treatment and diagnosis for cancer therapy. The specific activities were as follows:
1) An exosome as a novel diagnosis and therapeutic tool against cancer;
2) Drug discovery for targeting miRNA to regulate cancer stem cell properties;
3) Development of carcinogenic model using tissue stem cell culture; and
4) Small molecule-based reprogramming of human hepatocytes modelling for hepatocellular carcinomas.
Research activities
1) Biological significance of exosomes and circulating miRNAs
We have identified "Malignant Exosomes" from highly metastatic gastric cancer cell lines, which remarkably induce the differentiation of cancer-associated fibroblasts (CAFs). Highly metastatic gastric cancer induced the expression of inflammatory cytokines in the CAFs, contributing to the CAF heterogeneity in gastric cancer.
By targeting circulating miRNAs in blood, we have established highly accurate cancer detection systems in several types of cancer. For sarcoma detection, seven miRNA combinations can distinguish sarcomas from benign and healthy controls (Asano et al., Nature communications, 2019). For ovarian cancer, combining nine to ten miRNA combination detected ovarian cancer patients from healthy controls and other types of cancer patients (Yokoi et al., Nature communications, 2018). In prostate cancer patients, two miRNA combinations make accurate detection of prostate cancer from benign controls (Urabe et al., Clinical Cancer Research, 2019).
2) Drug discovery for targeting miRNA to regulate cancer stem cell property
While cancer stem cell (CSC) properties such as tumorigenicity and drug resistance are a major focus in current cancer research, the molecular mechanisms for the regulation of CSC properties are not fully understood. MicroRNA (miRNA) is identified as the targets involved in the regulation of CSC properties. We previously identified microRNA-27b (miR-27b) as a key regulator for the generation of a side-population in breast cancer cells that showed CSC properties, and also found that the anti-type II diabetes (T2D) drug metformin reduced this side-population via miR-27b-mediated repression of ENPP1, which is involved in T2D development. We have begun the development of a mimic (mimetic nucleic acid) delivery system for miR-27b. Using the system, we have confirmed that miR-27b mimic was successfully delivered into the tumor in tumor-bearing mice.
3) Development for carcinogenic model using tissue stem cell culture
By applying a stable culturing system of human epithelial stem cells, we have established epithelial stem cell culture from lung biopsy. Based on the primary cell culture system, we are currently investigating tissue-specific oncogenic activities and also searched for small molecules and drugs that can selectively kill or damage cancer cells which harbor specific mutations.
4) Small molecule-based reprogramming of human hepatocytes modelling for hepatocellular carcinomas
We are interested in modelling hepatocellular carcinomas utilizing chemically induced liver progenitor cells. By modifying the technique to reprogram cancer cells, we have developed the strategy that a small molecular cocktail enabled a mature mouse and rat hepatocytes to reprogram bi-potential liver progenitor cells with high efficiency. Also, we succeeded to induce the reprogramming from human hepatocytes. Combining these techniques, our main focus is on the elucidation of the multi-step carcinogenesis process of normal liver cells to hepatocellular carcinomas.
Education
We have trained 11 Ph.D students.
Future prospects
1. Exosome Diagnosis and Treatment Strategy: We aim to develop novel diagnostic methods and new therapeutic methods in various cancer types for exosomes. We filed the patent applications for the intellectual property.
2. Cancer stem cells and miRNA: We aim to create new drugs targeting miRNAs that control cancer stem cells.
3. We aim to identify candidate factors for treatment and find out cancer stem cells by reproducing the process of carcinogenesis of cells from normal cancer cells through precancerous lesions.
4. We will continue elucidating the properties of new stem cells by studying hepatic stem cells and mesenchymal stem cells for developing a model of hepatocellular carcinomas.
List of papers published in 2018
Journal
1. Asano N, Matsuzaki J, Ichikawa M, Kawauchi J, Takizawa S, Aoki Y, Sakamoto H, Yoshida A, Kobayashi E, Tanzawa Y, Nakayama R, Morioka H, Matsumoto M, Nakamura M, Kondo T, Kato K, Tsuchiya N, Kawai A, Ochiya T. A serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes. Nat Commun, 10:1299, 2019
2. Kohama I, Kosaka N, Chikuda H, Ochiya T. An Insight into the Roles of MicroRNAs and Exosomes in Sarcoma. Cancers (Basel), 11:E428, 2019
3. Kosaka N, Kogure A, Yamamoto T, Urabe F, Usuba W, Prieto-Vila M, Ochiya T. Exploiting the message from cancer: the diagnostic value of extracellular vesicles for clinical applications. Exp Mol Med, 51:31, 2019
4. Shimomura I, Yamamoto Y, Ochiya T. Synthetic Lethality in Lung Cancer-From the Perspective of Cancer Genomics. Medicines (Basel), 6:E38, 2019
5. Shigemizu D, Akiyama S, Asanomi Y, Boroevich KA, Sharma A, Tsunoda T, Matsukuma K, Ichikawa M, Sudo H, Takizawa S, Sakurai T, Ozaki K, Ochiya T, Niida S. Risk prediction models for dementia constructed by supervised principal component analysis using miRNA expression data. Commun Biol, 2:77, 2019
6. Kogure A, Kosaka N, Ochiya T. Cross-talk between cancer cells and their neighbors via miRNA in extracellular vesicles: an emerging player in cancer metastasis. J Biomed Sci, 26:7, 2019
7. Katsuda T, Ochiya T, Sakai Y. Generation of Hepatic Organoids with Biliary Structures. Methods Mol Biol, 175-185, 2019
8. Katsuda T, Ochiya T. Chemically Induced Liver Progenitors (CLiPs): A Novel Cell Source for Hepatocytes and Biliary Epithelial Cells. Methods Mol Biol, 117-130, 2019
9. Shiino S, Matsuzaki J, Shimomura A, Kawauchi J, Takizawa S, Sakamoto H, Aoki Y, Yoshida M, Tamura K, Kato K, Kinoshita T, Kitagawa Y, Ochiya T. Serum miRNA-based Prediction of Axillary Lymph Node Metastasis in Breast Cancer. Clin Cancer Res, 25:1817-1827, 2019
10. Usuba W, Urabe F, Yamamoto Y, Matsuzaki J, Sasaki H, Ichikawa M, Takizawa S, Aoki Y, Niida S, Kato K, Egawa S, Chikaraishi T, Fujimoto H, Ochiya T. Circulating miRNA panels for specific and early detection in bladder cancer. Cancer Sci, 110:408-419, 2019
11. Fujiwara Y, Saito M, Robles AI, Nishida M, Takeshita F, Watanabe M, Ochiya T, Yokota J, Kohno T, Harris CC, Tsuchiya N. A Nucleolar Stress-Specific p53-miR-101 Molecular Circuit Functions as an Intrinsic Tumor-Suppressor Network. EBioMedicine, 33:33-48, 2018
12. Miyazaki M, Otomo R, Matsushima-Hibiya Y, Suzuki H, Nakajima A, Abe N, Tomiyama A, Ichimura K, Matsuda K, Watanabe T, Ochiya T, Nakagama H, Sakai R, Enari M. The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas. Cell Death Discov, 4:56, 2018
13. Clayton A, Buschmann D, Byrd JB, Carter DRF, Cheng L, Compton C, Daaboul G, Devitt A, Falcon-Perez JM, Gardiner C, Gustafson D, Harrison P, Helmbrecht C, Hendrix A, Hill A, Hoffman A, Jones JC, Kalluri R, Kang JY, Kirchner B, Lasser C, Lawson C, Lenassi M, Levin C, Llorente A, Martens-Uzunova ES, Moller A, Musante L, Ochiya T, Pink RC, Tahara H, Wauben MHM, Webber JP, Welsh JA, Witwer KW, Yin H, Nieuwland R. Summary of the ISEV workshop on extracellular vesicles as disease biomarkers, held in Birmingham, UK, during December 2017. J Extracell Vesicles, 7:1473707, 2018
14. Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Bedina Zavec A, Benmoussa A, Berardi AC, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borras FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan MA, Brigstock DR, Brisson A, Broekman ML, Bromberg JF, Bryl-Gorecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzas EI, Byrd JB, Camussi G, Carter DR, Caruso S, Chamley LW, Chang YT, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FA, Coyle B, Crescitelli R, Criado MF, D'Souza-Schorey C, Das S, Datta Chaudhuri A, de Candia P, De Santana EF, De Wever O, Del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TA, Duarte FV, Duncan HM, Eichenberger RM, Ekstrom K, El Andaloussi S, Elie-Caille C, Erdbrugger U, Falcon-Perez JM, Fatima F, Fish JE, Flores-Bellver M, Forsonits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gamez-Valero A, Gardiner C, Gartner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DC, Gorgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, Ibrahim AGE, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Kano SI, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ, Kornek M, Kosanovic MM, Kovacs AF, Kramer-Albers EM, Krasemann S, Krause M, Kurochkin IV, Kusuma GD, Kuypers S, Laitinen S, Langevin SM, Languino LR, Lannigan J, Lasser C, Laurent LC, Lavieu G, Lazaro-Ibanez E, Le Lay S, Lee MS, Lee YXF, Lemos DS, Lenassi M, Leszczynska A, Li IT, Liao K, Libregts SF, Ligeti E, Lim R, Lim SK, Line A, Linnemannstons K, Llorente A, Lombard CA, Lorenowicz MJ, Lorincz AM, Lotvall J, Lovett J, Lowry MC, Loyer X, Lu Q, Lukomska B, Lunavat TR, Maas SL, Malhi H, Marcilla A, Mariani J, Mariscal J, Martens-Uzunova ES, Martin-Jaular L, Martinez MC, Martins VR, Mathieu M, Mathivanan S, Maugeri M, McGinnis LK, McVey MJ, Meckes DGJ, Meehan KL, Mertens I, Minciacchi VR, Moller A, Moller Jorgensen M, Morales-Kastresana A, Morhayim J, Mullier F, Muraca M, Musante L, Mussack V, Muth DC, Myburgh KH, Najrana T, Nawaz M, Nazarenko I, Nejsum P, Neri C, Neri T, Nieuwland R, Nimrichter L, Nolan JP, Nolte-'t Hoen EN, Noren Hooten N, O'Driscoll L, O'Grady T, O'Loghlen A, Ochiya T, Olivier M, Ortiz A, Ortiz LA, Osteikoetxea X, Ostergaard O, Ostrowski M, Park J, Pegtel DM, Peinado H, Perut F, Pfaffl MW, Phinney DG, Pieters BC, Pink RC, Pisetsky DS, Pogge von Strandmann E, Polakovicova I, Poon IK, Powell BH, Prada I, Pulliam L, Quesenberry P, Radeghieri A, Raffai RL, Raimondo S, Rak J, Ramirez MI, Raposo G, Rayyan MS, Regev-Rudzki N, Ricklefs FL, Robbins PD, Roberts DD, Rodrigues SC, Rohde E, Rome S, Rouschop KM, Rughetti A, Russell AE, Saa P, Sahoo S, Salas-Huenuleo E, Sanchez C, Saugstad JA, Saul MJ, Schiffelers RM, Schneider R, Schoyen TH, Scott A, Shahaj E, Sharma S, Shatnyeva O, Shekari F, Shelke GV, Shetty AK, Shiba K, Siljander PRM, Silva AM, Skowronek A, Snyder OL, Soares RP, Sodar BW, Soekmadji C, Sotillo J, Stahl PD, Stoorvogel W, Stott SL, Strasser EF, Swift S, Tahara H, Tewari M, Timms K, Tiwari S, Tixeira R, Tkach M, Toh WS, Tomasini R, Torrecilhas AC, Tosar JP, Toxavidis V, Urbanelli L, Vader P, van Balkom BW, van der Grein SG, Van Deun J, van Herwijnen MJ, Van Keuren-Jensen K, van Niel G, van Royen ME, van Wijnen AJ, Vasconcelos MH, Vechetti IJJ, Veit TD, Vella LJ, Velot E, Verweij FJ, Vestad B, Vinas JL, Visnovitz T, Vukman KV, Wahlgren J, Watson DC, Wauben MH, Weaver A, Webber JP, Weber V, Wehman AM, Weiss DJ, Welsh JA, Wendt S, Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan X, Yanez-Mo M, Yin H, Yuana Y, Zappulli V, Zarubova J, Zekas V, Zhang JY, Zhao Z, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba-Surma EK. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles, 7:1535750, 2018
15. Fujita Y, Kadota T, Araya J, Ochiya T, Kuwano K. Clinical Application of Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapeutics for Inflammatory Lung Diseases. J Clin Med, 7:E355, 2018
16. Ageta H, Ageta-Ishihara N, Hitachi K, Karayel O, Onouchi T, Yamaguchi H, Kahyo T, Hatanaka K, Ikegami K, Yoshioka Y, Nakamura K, Kosaka N, Nakatani M, Uezumi A, Ide T, Tsutsumi Y, Sugimura H, Kinoshita M, Ochiya T. UBL3 modification influences protein sorting to small extracellular vesicles. Nat Commun, 9:3936, 2018
17. Yoshioka Y, Katsuda T, Ochiya T. Extracellular vesicles and encapusulated miRNAs as emerging cancer biomarkers for novel liquid biopsy. Jpn J Clin Oncol, 48:869-876, 2018
18. Matsuzaki J, Ochiya T. Extracellular microRNAs and oxidative stress in liver injury: a systematic mini review. J Clin Biochem Nutr, 63:6-11, 2018
19. Kanda Y, Kawaguchi T, Osaki M, Onuma K, Ochiya T, Kitagawa T, Okada F. Fascin protein stabilization by miR-146a implicated in the process of a chronic inflammation-related colon carcinogenesis model. Inflamm Res, 67:839-846, 2018
20. Naito Y, Hamada-Tsutsumi S, Yamamoto Y, Kogure A, Yoshioka Y, Watashi K, Ochiya T, Tanaka Y. Screening of microRNAs for a repressor of hepatitis B virus replication. Oncotarget, 9:29857- 29868, 2018
21. Otsuka K, Yamamoto Y, Ochiya T. Regulatory role of resveratrol, a microRNA-controlling compound, in HNRNPA1 expression, which is associated with poor prognosis in breast cancer. Oncotarget, 9:24718-24730, 2018
22. Sanchez Calle A, Kawamura Y, Yamamoto Y, Takeshita F, Ochiya T. Emerging roles of long non-coding RNA in cancer. Cancer Sci, 109:2093-2100, 2018
23. Gailhouste L, Liew LC, Yasukawa K, Hatada I, Tanaka Y, Nakagama H, Ochiya T. Differentiation Therapy by Epigenetic Reconditioning Exerts Antitumor Effects on Liver Cancer Cells. Mol Ther, 26:1840-1854, 2018
24. Urabe F, Kosaka N, Kimura T, Egawa S, Ochiya T. Extracellular vesicles: Toward a clinical application in urological cancer treatment. Int J Urol, 25:533-543, 2018
25. Yukawa H, Suzuki K, Aoki K, Arimoto T, Yasui T, Kaji N, Ishikawa T, Ochiya T, Baba Y. Imaging of angiogenesis of human umbilical vein endothelial cells by uptake of exosomes secreted from hepatocellular carcinoma cells. Sci Rep, 8:6765, 2018
26. Gailhouste L, Liew LC, Hatada I, Nakagama H, Ochiya T. Epigenetic reprogramming using 5-azacytidine promotes an anti-cancer response in pancreatic adenocarcinoma cells. Cell Death Dis, 9:468, 2018
27. Shiozawa K, Yoshioka Y, Qiao Z, Shuting J, Ochiya T, Kondo T. Pazopanib-induced changes in protein expression signatures of extracellular vesicles in synovial sarcoma. Biochem Biophys Res Commun, 506:723-730, 2018
28. Yokoi A, Matsuzaki J, Yamamoto Y, Yoneoka Y, Takahashi K, Shimizu H, Uehara T, Ishikawa M, Ikeda SI, Sonoda T, Kawauchi J, Takizawa S, Aoki Y, Niida S, Sakamoto H, Kato K, Kato T, Ochiya T. Integrated extracellular microRNA profiling for ovarian cancer screening. Nat Commun, 9:4319, 2018
Book
1. Yamamoto Y, Calle AS, Ochiya T. Single Cell Genomics. In: Santra T, Tseng FG (ed), Handbook of Single Cell Technologies, Singapore, Springer, 2018
2. Prieto-Vila M, Yamamoto Y, Takahashi R, Ochiya T. Single-Cell Transcriptomics. In: Santra T, Tseng FG (ed), Handbook of Single Cell Technologies, Singapore, Springer, 2018