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  2. Sugihara Eiji

Sugihara Eiji

  (杉原 英志)

Profile Information

Affiliation
Fujita Health University
Visiting Associate Professor, R&D Center for Precision Medicine, University of Tsukuba
Adjunct Associate Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center
Degree
M.S. in medical sicence(University of Tsukuba)
Ph.D. in medicine(University of Tsukuba)
Researcher number
50464996
ORCID ID
 https://orcid.org/0000-0002-3233-1045
J-GLOBAL ID
200901078177382512
researchmap Member ID
6000007508

Current Research Projects:

  1. Elucidation of the unique characteristics of relapsed and refractory cancers, and the development of therapeutic strategies based on these findings
  2. Development of novel cancer stratification methods and diagnostic technologies
  3. Investigation of the mechanisms underlying functional coordination and regulation across diverse cell types and organ systems

We have been studying the functional role of the oncogene MYC in cancers1-2. Through the development of mouse cancer models in various tissues, we have uncovered key molecular mechanisms by which abnormalities in cancer-related genes cause carcinogenesis from normal stem, progenitor, and differentiated cells3–8 and how cancer cells acquire resistance to immune responses9,10. More recently, we have also contributed to the advancement of cancer genome analysis by establishing techniques to detect genomic alterations and structural variants using next-generation and long-read sequencing technologies11-13.

Currently, our research is centered on identifying the distinct biological processes that drive cancer malignancy from both basic science and clinical viewpoints. We place particular emphasis on aggressive, relapsed, and therapy-resistant cancers. Using a combination of clinical specimens, cell lines, and organoid models, we apply genomic and transcriptomic analysis, molecular and cellular biology techniques, and animal models to explore these complex questions. We are committed to pursuing any unexplored or biologically intriguing challenge in cancer biology.

If you are interested in our research, please feel free to contact me at eijisugihara77[at]gmail.com (replace [at] with @).
We are currently recruiting graduate students.

(1)Sugihara E et al Oncogene 2004, (2)Sugihara E et al Cancer Res 2006, (3)Sugihara E et al Oncogene 2011, (4)Sampetrean O et al 2011, (5)Shimizu T et al Cancer Res, (6)Adachi T et al Nat Med 2014, (7)Ishizawa J et al Blood 2017, (8)Semba T et al Cancer Sci 2018, (9)Sugihara E et al Cancer Res 2020, (10)Ueno S et al Commun Biol 2022, (11)Kakiuchi N Nat 2020, (12)Chikaishi Y Cancer Sci 2025 (13)Mariya T et al J Hum Genet. 2022.

Research Interests

 12

Research Areas

 5

Research History

 11
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Education

 3

Committee Memberships

 1

Awards

 10
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Major Papers

 93
  • Yuko Chikaishi, Hiroshi Matsuoka, Eiji Sugihara, Mayu Takeda, Makoto Sumitomo, Seiji Yamada, Gaku Inaguma, Yusuke Omura, Yeongcheol Cheong, Yosuke Kobayashi, Masaya Nakauchi, Junichiro Hiro, Koji Masumori, Koki Otsuka, Hiroshi Nishihara, Koichi Suda, Hideyuki Saya, Tetsuya Takimoto
    Cancer science, Jan 16, 2025  
    Colorectal cancer (CRC) is well characterized in terms of genetic mutations and the mechanisms by which they contribute to carcinogenesis. Mutations in APC, TP53, and KRAS are common in CRC, indicating key roles for these genes in tumor development and progression. However, for certain tumors with low frequencies of these mutations that are defined by tumor location and molecular phenotypes, a carcinogenic mechanism dependent on BRAF mutations has been proposed. We here analyzed targeted sequence data linked to clinical information for CRC, focusing on tumors with a high tumor mutation burden (TMB) in order to identify the characteristics of associated mutations, their relations to clinical features, and the mechanisms of carcinogenesis in tumors lacking the major driver oncogenes. Analysis of overall mutation frequencies confirmed that APC, TP53, and KRAS mutations were the most prevalent in our cohort. Compared with other tumors, TMB-high tumors were more frequent on the right side of the colon, had lower KRAS and higher BRAF mutation frequencies as well as a higher microsatellite instability (MSI) score, and showed a greater contribution of a mutational signature associated with MSI. Ranking of variant allele frequencies to identify genes that play a role early in carcinogenesis suggested that mutations in genes related to the DNA damage response (such as ATM and POLE) and to MSI (such as MSH2 and MSH6) may precede BRAF mutations associated with activation of the serrated pathway in TMB-high tumors. Our results thus indicate that TMB-high tumors suggest that mutations of genes related to mismatch repair and the DNA damage response may contribute to activation of the serrated pathway in CRC.
  • Taku Kato, Eiji Sugihara, Yuko Hata, Kyojiro Kawakami, Yasunori Fujita, Kosuke Mizutani, Tatsuya Ando, Yasuhiro Sakai, Kouhei Sakurai, Shohei Toyota, Hidetoshi Ehara, Masafumi Ito, Hiroyasu Ito
    The Prostate, Sep 15, 2024  
    BACKGROUND: Androgen receptor signaling inhibitors(ARSIs) have been used to treat patients with metastatic prostate cancer (PC) and castration-resistant prostate cancer (CRPC). In this study, we aimed to identify novel serum extracellular vesicle (EV)-based biomarkers to diagnose ARSI-resistance and therapeutic targets for ARSI-resistant CRPC. METHODS: Total RNA contained in serum EVs from 5 cases of CRPC before ARSI treatment and after acquiring ARSI-resistance was subjected to RNA-sequencing. The expression changes of selected RNAs contained in EVs were confirmed in 48 cases of benign prostatic hyperplasia (BPH) and 107 PC using reverse transcription-quantitative PCR (RT-qPCR) and compared with tissue RNA expression using public datasets. RESULTS: RNA-sequencing revealed that mitochondrial oxidative phosphorylation (OXPHOS)-related genes were increased in EVs after acquiring ARSI-resistance. Among them, RT-qPCR and datasets analysis demonstrated that SDHB mRNA was upregulated after acquiring ARSI-resistance in EVs and ARSI-exposed PC tissue compared to ARSI-naïve EVs and tissue, respectively. SDHB mRNA levels both in EVs and tissue were increased in localized PC compared with BPH and decreased in advanced PC. Tissue expression of SDHB mRNA was significantly correlated with those of other OXPHOS-related genes. SDHB mRNA in EVs (EV-SDHB) was elevated among 3 out of 7 ARSI-treating patients with stable PSA levels who later progressed to ARSI-resistant CRPC. CONCLUSIONS: The levels of OXPHOS-related mRNAs in EVs correlated with those in PC tissue, among which SDHB mRNA was found to be a novel biomarker to diagnose ARSI-resistance. EV-SDHB may be useful for early diagnosis of ARSI-resistance.
  • Sayaka Ueno, Tamotsu Sudo, Hideyuki Saya, Eiji Sugihara
    Communications biology, 5(1) 904-904, Sep 2, 2022  Peer-reviewedLast authorCorresponding author
    Peritoneal dissemination of ovarian cancer (OC) correlates with poor prognosis, but the mechanisms underlying the escape of OC cells from the intraperitoneal immune system have remained unknown. We here identify pigment epithelium-derived factor (PEDF) as a promoting factor of OC dissemination, which functions through induction of CD206+ Interleukin-10 (IL-10)-producing macrophages. High PEDF gene expression in tumors is associated with poor prognosis in OC patients. Concentrations of PEDF in ascites and serum are significantly higher in OC patients than those with more benign tumors and correlated with early recurrence of OC patients, suggesting that PEDF might serve as a prognostic biomarker. Bromodomain and extraterminal (BET) inhibitors reduce PEDF expression and limit both OC cell survival and CD206+ macrophage induction in the peritoneal cavity. Our results thus implicate PEDF as a driver of OC dissemination and identify a BET protein-PEDF-IL-10 axis as a promising therapeutic target for OC.
  • Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Nobuyuki Kakiuchi, Tetsuichi Yoshizato, Andrew T Lenis, Shigekatsu Maekawa, Akira Yokoyama, Yasuhide Takeuchi, Yoshikage Inoue, Yotaro Ochi, Yusuke Shiozawa, Kosuke Aoki, Kenichi Yoshida, Keisuke Kataoka, Masahiro M Nakagawa, Yasuhito Nannya, Hideki Makishima, Jimpei Miyakawa, Taketo Kawai, Teppei Morikawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Genta Nagae, Masashi Sanada, Eiji Sugihara, Taka-Aki Sato, Tohru Nakagawa, Masashi Fukayama, Tetsuo Ushiku, Hiroyuki Aburatani, Satoru Miyano, Jonathan A Coleman, Yukio Homma, David B Solit, Haruki Kume, Seishi Ogawa
    Cancer cell, 39(6) 793-809, Jun 14, 2021  Peer-reviewed
    Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.
  • Eiji Sugihara, Norisato Hashimoto, Satoru Osuka, Takatsune Shimizu, Sayaka Ueno, Shogo Okazaki, Tomonori Yaguchi, Yutaka Kawakami, Kenjiro Kosaki, Taka-Aki Sato, Shinichiro Okamoto, Hideyuki Saya
    Cancer research, 80(20) 4439-4450, Oct 15, 2020  Peer-reviewedLead authorCorresponding author
    Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.
  • Nobuyuki Kakiuchi, Kenichi Yoshida, Motoi Uchino, Takako Kihara, Kotaro Akaki, Yoshikage Inoue, Kenji Kawada, Satoshi Nagayama, Akira Yokoyama, Shuji Yamamoto, Minoru Matsuura, Takahiro Horimatsu, Tomonori Hirano, Norihiro Goto, Yasuhide Takeuchi, Yotaro Ochi, Yusuke Shiozawa, Yasunori Kogure, Yosaku Watatani, Yoichi Fujii, Soo Ki Kim, Ayana Kon, Keisuke Kataoka, Tetsuichi Yoshizato, Masahiro M Nakagawa, Akinori Yoda, Yasuhito Nanya, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Eiji Sugihara, Taka-Aki Sato, Takashi Maruyama, Hiroyuki Miyoshi, Makoto Mark Taketo, Jun Oishi, Ryosaku Inagaki, Yutaka Ueda, Shinya Okamoto, Hideaki Okajima, Yoshiharu Sakai, Takaki Sakurai, Hironori Haga, Seiichi Hirota, Hiroki Ikeuchi, Hiroshi Nakase, Hiroyuki Marusawa, Tsutomu Chiba, Osamu Takeuchi, Satoru Miyano, Hiroshi Seno, Seishi Ogawa
    Nature, 577(7789) 260-265, Jan, 2020  Peer-reviewed
    Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.
  • Takashi Semba, Eiji Sugihara, Nagisa Kamoshita, Sayaka Ueno, Keitaro Fukuda, Masafumi Yoshino, Kazumasa Takao, Kazunori Yoshikawa, Kenji Izuhara, Yoshimi Arima, Makoto Suzuki, Hideyuki Saya, Co, st author
    Cancer Science, 109(5) 1447-1454, May 1, 2018  Peer-reviewedLead authorCorresponding author
  • Jo Ishizawa, Eiji Sugihara, Shinji Kuninaka, Kaoru Mogushi, Kensuke Kojima, Christopher B. Benton, Ran Zhao, Dhruv Chachad, Norisato Hashimoto, Rodrigo O. Jacamo, Yihua Qiu, Suk Young Yoo, Shinichiro Okamoto, Michael Andreeff, Steven M. Kornblau, Hideyuki Saya
    BLOOD, 129(14) 1958-1968, Apr, 2017  Peer-reviewed
  • Walied Kamel, Eiji Sugihara, Hiroyuki Nobusue, Sayaka Yamaguchi-Iwai, Nobuyuki Onishi, Kenta Maki, Yumi Fukuchi, Koichi Matsuo, Akihiro Muto, Hideyuki Saya, Takatsune Shimizu
    MOLECULAR CANCER THERAPEUTICS, 16(1) 182-192, Jan, 2017  Peer-reviewed
  • Takeya Adachi, Tetsuro Kobayashi, Eiji Sugihara, Taketo Yamada, Koichi Ikuta, Stefania Pittaluga, Hideyuki Saya, Masayuki Amagai, Keisuke Nagao
    Nature Medicine, 21(11) 1272-1279, Oct, 2015  Peer-reviewed
  • Keitaro Fukuda, Eiji Sugihara, Shoichiro Ohta, Kenji Izuhara, Takeru Funakoshi, Masayuki Amagai, Hideyuki Saya
    PLOS ONE, 10(6) e0129704, Jun, 2015  Peer-reviewed
  • E. Sugihara, T. Shimizu, K. Kojima, N. Onishi, K. Kai, J. Ishizawa, K. Nagata, N. Hashimoto, H. Honda, M. Kanno, M. Miwa, S. Okada, M. Andreeff, H. Saya
    ONCOGENE, 31(23) 2849-2861, Jun, 2012  Peer-reviewedLead author
  • E Sugihara, M Kanai, S Saito, T Nitta, H Toyoshima, K Nakayama, KI Nakayama, K Fukasawa, M Schwab, H Saya, M Miwa
    CANCER RESEARCH, 66(8) 4020-4029, Apr, 2006  Peer-reviewedLead author
  • E Sugihara, M Kanai, A Matsui, M Onodera, M Schwab, M Miwa
    ONCOGENE, 23(4) 1005-1009, Jan, 2004  Peer-reviewedLead author
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Misc.

 38

Major Books and Other Publications

 1
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Presentations

 78
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Professional Memberships

 5

Research Projects

 14
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Industrial Property Rights

 1
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