Current Research

Overcoming adaptive therapeutic resistance in malignant brain tumors

Many subtypes of brain tumors are highly malignant and resistant to chemo- and radio- therapy. Radiotherapy is the most frequently used treatment modality and is effective for many types of brain tumors, but it has not prevented recurrence in aggressive types of malignant brain tumors such as Glioblastoma (GBM) and Medulloblastoma (MB). To understand the radioresistance mechanisms, researchers have been investigating the response of brain tumors to short periods of radiation therapy. They have been useful for investigating the mechanisms of innate resistance, but not for investigating the mechanisms of adaptive resistance to long-term treatment, as is used in clinical practice. The mechanism of adaptive resistance in malignant brain tumors is still poorly understood, and effective treatments for it have not yet been developed.

To address the problem, we have developed unique new experimental models to identify the adaptive resistance mechanisms to fractionated radiation. We established radioresistant subpopulations of brain tumor cells after repeated irradiation (2 or 5Gy every 3-4 days, 3-6 weeks). In studying these cells, we have already discovered one novel adaptive resistance mechanism driven by increase in IGF1 and N-cadherin expression, which was published in the Journal of Clinical Investigation. To expand on the above successful trajectory, we will use a genome-wide CRISPR library screening approach and humanized mice models to more comprehensively identify pathways of adaptive resistance in Glioblastoma and other brain tumors.

Investigate the adaptive resistance mechanisms related to the immune-stroma microenvironment in Glioblastoma by using humanized mice model

To understand the adaptive resistance mechanisms of GBM, we need to use appropriate animal models which recapitulate the molecular, immunological, and histological characteristics of GBM. Although there are substantial advances in developing such models, including syngeneic, xenogeneic, and genetically engineered mice, these GBMs were formed without a human immune environment. To overcome this critical issue, we established new GBM xenograft models in humanized mice in collaboration with Dr. Masakazu Kamata. We used NSG and NSG-SGM3 mice engrafted with human hematopoietic stem cells, which develop functional cellular components of the human immune system. We have confirmed that NSG humanized mice allow for GBM xenograft formation, and the tumors display infiltration with various lineages of human immune cells. We believe our innovative research will create a new model, opening new avenues for GBM research. This model will be helpful for accurately assessing the effects of immunotherapy and other therapies before clinical studies, which will significantly benefit brain tumor patients.

Selected Publications

Complete List of Published Work in Pubmed or Google Scholar

  1. Nakata S, Murai J, Okada M, Takahashi H, Findlay TH, Malebranche K, Parthasarathy A, Miyashita S, Gabdulkhaev R, Benkimoun I, Druillennec S, Chabi S, Hawkins E, Miyahara H, Tateishi K, Yamashita S, Yamada S, Saito T, On J, Watanabe J, Tsukamoto Y, Yoshimura J, Oishi M, Nakano T, Imamura M, Imai C, Yamamoto T, Takeshima H, Sasaki AT, Rodriguez FJ, Nobusawa S, Varlet P, Pouponnot C, Osuka S, Pommier Y, Kakita A, Fujii Y, Raabe EH, Eberhart CG, Natsumeda M. Epigenetic upregulation of Schlafen11 renders WNT- and SHH- activated medulloblastomas sensitive to cisplatin. Neuro Oncol. 2022 Oct 23:noac243. doi: 10.1093/neuonc/noac243. Epub ahead of print. PMID: 36273330.
  2. Daddacha W, Monroe D, Carver K, Usoro E, Alptekin A, Xu H, Osuka S, Arbab AS, Sakamuro D, Viral particle-mediated SAMHD1 depletion sensitizes refractory glioblastoma to DNA-damaging therapeutics by impairing homologous recombination. Cancers, 2022, Epub ahead of print.
  3. Estep BK, Kuhlmann CJ, Osuka S, Suryavanshi GW, Nagaoka-Kamata Y, Samuel CN, Blucas MT, Jepson CE, Goepfert PA, Kamata M, Skewed Fate and Hematopoiesis of CD34+ HSPCs in Umbilical Cord Blood Amid the COVID-19 Pandemic. iScience, Nov 11;105544, 2022.
  4. Osuka S. Targeting adaptive radioresistance in Glioblastoma. Neuro-Oncology. 24(7):1071-1073, 2022.
  5. Kaluz S, Zhang Q, Kuranaga Y, Yang H, Osuka S, Bhattacharya D, Devi SN, Mun J, Wang W, Zhang R, Goodman MM, Grossniklaus HE, Van Meir EG, Targeting HIF-activated collagen prolyl 4-hydroxylase expression disrupts collagen deposition and blocks primary and metastatic uveal melanoma growth. Oncogene. 40(33):5182-5191, 2021.
  6. Osuka S (co-corresponding), Zhu D, Zhang Z, Li C, Stackhouse CT, Sampetrean O, Olson JJ, Gillespie GY, Saya H, Willey CD, Van Meir EG, N-cadherin upregulation mediates adaptive radioresistance in glioblastoma. J Clin Invest. 2021;131(6):e136098. https://doi.org/10.1172/JCI136098. *Top read articles in the Journal of Clinical Investigation (April, 2021) *Highlighted in Neuro-Oncology. 2021,23:1228
  7. Sugihara E, Hashimoto N, Osuka S, Shimizu T, Ueno S, Okazaki S, Yaguchi T, Kawakami Y, Kosaki K, Sato TA, Okamoto S, 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
  8. Lee SH, Khwaja FW, Tyler K, Yu B, Zhang Z, Osuka S, Zerrouqi A, Kaluzova M, Hadjipanayis CG, Cummings RD, Olson JJ, Devi NS, and Van Meir EG, A Chimeric Signal Peptide-Galectin-3 Conjugate Induces Glycosylation-Dependent Cancer Cell-Specific Apoptosis. Clin Cancer Res. 1;26(11):2711-2724. 2020.
  9. Dong L, You S, Zhang Q, Osuka S, Devi N, Kaluz1 S, Holmes J, Yang H, Chen G, Wang B, Grossniklaus HE and Van Meir EG. Arylsulfonamide 64B inhibits hypoxia/HIF-induced expression of c-Met and CXCR4 and reduces tumor growth and metastasis of uveal melanoma. Clin Cancer Res. 1;25(7):2206-2218, 2019.
  10. Harusato A, Viennois E, Etienne-Mesmin L, Matsuyama S, Abo H, Osuka S, Lukacs N, Li JD, Merlin D, Gewirtz A, and Denning T. Early life microbiota exposure restricts myeloid-derived suppressor cell driven colonic tumorigenesis. Cancer Immunology Research. 7(4):544-551, 2019.
  11. Zhu D, Osuka S, Zhang Z, Reichert ZR, Yang L, Kanemura Y, Jiang Y, You S, Zhang H, Devi NS, Bhattacharya D, Takano S, Gillespie GY, Macdonald T, Tan C, Nishikawa R, Nelson WG, Olson JJ, Van Meir EG. BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation. Cancer Cell. 11;33(6):1004-1016, 2018.                                                                                                  
  12. Osuka S, Van Meir EG. Cancer therapy: Neutrophils traffic in cancer nanodrugs. Nature Nanotechnology. 12(7):616-618, 2017.                  
  13. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C, Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ, Ra YS, Kumabe T, López-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpeña-Diazconti M, Chico Ponce de León F, Robinson S, Zapotocky M, Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB, Rutka JT, Bader GD, Reimand J, Goldenberg A, Ramaswamy V, Taylor MD. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell. 12;31(6):737-754, 2017.                                       
  14. Miyazaki T, Ishikawa E, Matsuda M, Akutsu H, Osuka S, Sakamoto N, Takano S, Yamamoto T, Tsuboi K, Matsumura A. Assessment of PD-1 positive cells on initial and secondary resected tumor specimens of newly diagnosed glioblastoma and its implications on patient outcome. J Neurooncol. 133(2):277-285, 2017.            
  15. Osuka S, Van Meir EG. Overcoming therapeutic resistance in glioblastoma: the way forward. Journal of Clinical Investigation. J Clin Invest. 1;127(2):415-426, 2017. Review                                   
  16. Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW, Jones DT, Luu B, Cavalli FM, Aldape K, Remke M, Mynarek M, Rutkowski S, Gururangan S, McLendon RE, Lipp ES, Dunham C, Hukin J, Eisenstat DD, Fulton D, van Landeghem FK, Santi M, van Veelen MC, Van Meir EG, Osuka S, Fan X, Muraszko KM, Tirapelli DP, Oba-Shinjo SM, Marie SK, Carlotti CG, Lee JY, Nageswara Rao AA, Giannini C, Faria CC, Nunes S, Mora J, Hamilton RL, Hauser P, Jabado N, Petrecca K, Jung S, Massimi L, Zollo M, Cinalli G, Bognár L, Klekner A, Hortobágyi T, Leary S, Ermoian RP, Olson JM, Leonard JR, Gardner C, Grajkowska WA, Chambless LB, Cain J, Eberhart CG, Ahsan S, Massimino M, Giangaspero F, Buttarelli FR, Packer RJ, Emery L, Yong WH, Soto H, Liau LM, Everson R, Grossbach A, Shalaby T, Grotzer M, Karajannis MA, Zagzag D, Wheeler H, von Hoff K, Alonso MM, Tuñon T, Schüller U, Zitterbart K, Sterba J, Chan JA, Guzman M, Elbabaa SK, Colman H, Dhall G, Fisher PG, Fouladi M, Gajjar A, Goldman S, Hwang E, Kool M, Ladha H, Vera-Bolanos E, Wani K, Lieberman F, Mikkelsen T, Omuro AM, Pollack IF, Prados M, Robins HI, Soffietti R, Wu J, Metellus P, Tabori U, Bartels U, Bouffet E, Hawkins CE, Rutka JT, Dirks P, Pfister SM, Merchant TE, Gilbert MR, Armstrong TS, Korshunov A, Ellison DW, Taylor MD. Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol. 20;34(21):2468-77, 2016.                       
  17. Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Gururangan S, McLendon RE, Bigner D, Lipp ES, Perreault S, Cho YJ, Grant G, Kim SK, Lee JY, Rao AN, Giannini C, Li KK, Ng HK, Yao Y, Kumabe T, Tominaga T, Grajkowska WA, Perek-Polnik M, Low DC, Seow WT, Chang K, Mora J, Pollack IF, Hamilton RL, Leary S, Ermoian RP, Moore A, Ingram W, Hallahan AR, Jouvet A, Fevre-Montange M, Vasiljevic A, Faure-Conter C, Shofuda T, Kagawa N, Hashimoto N, Jabado N, Weil AG, Gayden T, Wataya T, Shalaby T, Grotzer M, Zitterbart K, Sterba J, Kren L, Hortobagyi T, Klekner A, Laszlo B, Pocza T, Hauser P, Schuller U, Jung S, Jang WY, French PJ, Kros JM, Van Veelen ML, Massimi L, Leonard JR, Rubin JB, Vibhakar R, Chambless LB, Cooper MK, Thompson RC, Faria CC, Carvalho A, Nunes S, Pimentel J, Fan X, Muraszko K, Lopez-Aguilar E, Garzia L, Shih D, Kijima N, Schneider C, Adamski J, Northcott PA, Kool M, Jones DT, Chan JA, Nikolic A, Garre ML, Van Meir EG, Osuka S, Olson JJ, Jahangiri A, Gupta N, Weiss WA, Moxon-Emre I, Mabbott DJ, Lassaletta A, Hawkins CE, Tabori U, Drake J, Kulkarni A, Dirks P, Rutka JT, Korshunov A, Pfister SM, Packer RJ, Ramaswamy V, Taylor MD. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: an integrated clinical and molecular analysis. Lancet Oncology. 17(4):484-95, 2016.
  18. Shimizu T, Sugihara E, Yamaguchi-Iwai S, Tamaki S, Koyama Y, Kamel W, Ueki A, Ishikawa T, Chiyoda T, Osuka S, Onishi N, Ikeda H, Kamei J, Matsuo K, Fukuchi Y, Nagai T, Toguchida J, Toyama Y, Muto A, Saya H. IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress. Cancer Res. 15;74(22):6531-41, 2014.     
  19. Saga I, Shibao S, Okubo J, Osuka S, Kobayashi Y, Yamada S, Fujita S, Urakami K, Kusuhara M, Yoshida K, Saya H, Sampetrean O. Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model. Neuro Oncol. 16(8):1048-56, 2014.                                            
  20. Uemae Y, Ishikawa E, Osuka S, Matsuda M, Sakamoto N, Takano S, Nakai K, Yamamoto T, Matsumura A. CXCL12 secreted from glioma stem cells regulates their proliferation. J Neurooncol. 117(1):43-51, 2014.                                
  21. Onuma K, Ishikawa E, Matsuda M, Hirata K, Osuka S, Yamamoto T, Masumoto T, Zaboronok A, Matsumura A. Clinical characteristics and neuroimaging findings in 12 cases of recurrent glioblastoma with communicating hydrocephalus. Neurol Med Chir (Tokyo). 53(7):474-81, 2013.                                                  
  22. Takano S, Kimu H, Tsuda K, Osuka S, Nakai K, Yamamoto T, Ishikawa E, Akutsu H, Matsuda M, Matsumura A. Decrease in the apparent diffusion coefficient in peritumoral edema for the assessment of recurrent glioblastoma treated by bevacizumab. Brain Edema XV. 118:185-9, 2013.                                                                
  23. Osuka S, Sampetrean O, Shimizu T, Saga I, Onishi N, Sugihara E, Okubo J, Fujita S, Takano S, Matsumura A, Saya H. IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. Stem Cells. 31:627-640, 2013.  
  24. Osuka S, Takano S, Watanabe S, Ishikawa E, Yamamoto T, Matsumura A, Valproic acid inhibits angiogenesis in vitro and glioma angiogenesis in vivo in the brain, Neurol Med Chir (Tokyo). 52(4):186-193, 2012