Hideyuki Saya

MD, PhD

CURRENT POSITION

  • Director, Oncology Innovation Center, Fujita Health University, Toyoake, Aichi, Japan
  • Emeritus Professor, Keio University, Tokyo, Japan

EDUCATIONS / TRAINING

1975-1981
Kobe University School of Medicine, Kobe, Japan (MD)

1983-1987
Kobe University Graduate School of Medicine, Kobe, Japan (PhD)

EXPERIENCES

1981-1983
Resident, Department of Neurosurgery, Kobe University School of Medicine, Kobe, Japan

1987-1988
Postdoctocal Fellow, Brain Tumor Research Center, University of California, San Francisco, CA, USA

1988-1994
Assistant Professor, Department of Neuro-Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

1994-2006
Professor, Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, Kumamoto, Japan

2007-2022
Professor, Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan

2015-2021
Vice President, Keio University Hospital

2022-present
Director, Oncology Innovation Center, Fujita Health University, Aichi, Japan

PUBLICATIONS

1. Sugihara E, Hashimoto N, Osuka S, Shimizu T, Ueno S, Okazaki S, Yaguchi T, Kawakami Y, Kosaki K, Sato TA, Okamoto S and Saya H: The inhibitor of apoptosis protein Livin confers resistance to Fas-mediated immune cytotoxicity in refractory lymphoma. Cancer Res 80(20):4439-4450, 2020

2. Takahashi N, Nobusue H, Shimizu T, Sugihara E, Yamaguchi-Iwai S, Onishi N, Kunitomi H, Kuroda T and Saya H: ROCK inhibition induces terminal adipocyte differentiation and suppresses tumorigenesis in chemoresistant osteosarcoma cells. Cancer Res 79: 3088-3099, 2019

3. Ishizawa J, Sugihara E, Kuninaka S, Mogushi K, Kojima K, Benton CB, Zhao R, Chachad D, Hashimoto N, Jacamo RO, Qiu Y, Yoo SY, Okamoto S, Andreeff M, Kornblau SM and Saya H: FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B cell acute leukemia. Blood 129: 1958-1968, 2017

4. Nobusue H, Onishi N, Shimizu T, Sugihara E, Oki Y, Sumikawa Y, Chiyoda T, Akashi K, Saya H and Kano K: Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation. Nat Commun 5: 3368, 2014

5. Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H, Osawa T, Kanki Y, Minami T, Aburatani H, Ohmura M, Kubo A, Suematsu M, Takahashi K, Saya H and Nagano O: Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat Commun 3: 883, 2012

6. Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H and Saya H: CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc- and thereby promotes tumor growth. Cancer Cell 19: 387-400, 2011

7. Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H and Hara E: Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 8: 1291-1297, 2006

8. Marumoto T, Zhang D and Saya H: Aurora A - A guardian of poles. Nat Rev Cancer 5:42-50, 2005

9. Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M, Hatakeyama K and Saya H: Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell 114: 585-598, 2003

10. Tanabe KK, Ellis LM and Saya H: Expression of the CD44R1 adhesion molecule is increased in human colon carcinomas and metastasis. Lancet 341: 725-726, 1993.

RESEARCH FOCUS

Our research focuses on the role of the IGF1-AKT signaling axis in promoting radioresistance in glioma stem cells (GSCs). We found that IGF1, secreted by differentiated glioma cells, activates AKT signaling in neighboring SOX2-positive GSCs, supporting their survival and maintenance under stress conditions, including radiation therapy.

This paracrine interaction creates a protective niche that enables a subset of GSCs to evade radiotherapy-induced damage, contributing to tumor recurrence.

Disruption of AKT signaling markedly sensitizes GSCs to radiation, both in vitro and in vivo, underscoring its critical role in radioresistance. Furthermore, clinical data reveal that high IGF1 expression correlates with poor prognosis in glioma patients, supporting the clinical relevance of this pathway.

These findings highlight the IGF1-AKT axis as a key mechanism of adaptive resistance in glioblastoma and suggest that targeting this pathway may improve the efficacy of radiotherapy by eliminating resistant GSC populations and suppressing tumor regrowth.

Adaptive radioprotection