Chris Hubert, Ph.D.
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
Phone: (216) 445-6471
Brain tumors can be among the most lethal cancers known, and are now the most frequent cause of cancer death in adolescents and young adults. Advanced brain tumors are driven by cancer stem cells and have extreme cellular diversity, with different independent tumor cell populations growing within distinct niche environments. This great diversity is part of the reason brain tumors are so difficult to treat. A brain tumor is therefore not just a mass of identical cancer cells, but rather a dynamic and diverse community of normal and cancer cell types functioning together in time and space. Many cancerous cells are so different from each other that their vulnerabilities must be discovered and attacked individually. We therefore believe the next evolution of brain cancer research will be driven by a more holistic recognition and understanding of the entire cell community present within tumors.
The Hubert Lab is exploring and exploiting the unique biology of the different cell populations within brain tumors. We use advanced, 3-dimensional, and patient-direct (not just patient-derived) models to study the brain tumor cell community with single-cell resolution. Our novel 3D organoid cultures, or “mini-tumors”, better recapitulate the diversity and microenvironmental biology of human tumors than traditional cultures. We have developed ways to isolate and functionally test cells from spatially distinct niches, and have leveraged this capability to identify unique and non-overlapping cancer vulnerabilities in different cell populations growing together in a tumor. We are now combining this data with novel 3D small molecule screening to pair multiple niche-specific targets with drugs that effectively shut these targets down. This allows us to create rationally-designed combination therapies to more completely eradicate the disease.
To truly change the outcomes for brain tumor patients, we must improve our ability to faithfully model and retain the cellular behaviors found within patient tumors, and we must be able to study these interacting cell populations at a granular level. Our lab is therefore focused on: A) developing brain tumor models that better mimic tumors within patients, B) studying cell-cell and cell-environment interplay within tumor stem cell niches, and C) the specific targeting and destruction of individual cell populations within brain tumors.
Our lab is focused on finding treatments for currently incurable advanced brain cancers. Part of the reason that advanced brain tumors are so hard to cure is that they contain many different kinds of cells in different locations working together to grow the tumor. Our usual lab models are grown on plastic and only represent a piece of all the cell types in a brain cancer. In a patient’s brain, cancer cells growing in different environments of the tumor can be so different from each other that we believe no one therapy will ever be able to kill them all. We are attacking this disease by first preserving the diversity of cells present in patients using 3-dimentional “mini-tumors” that retain different tumor environments as found in patients. We then study the different kinds of tumor cells in 3D, dividing up the complex tumor into smaller groups that we can treat and kill. By separately targeting essential pieces of each separate type of tumor cells, we are able to more completely destroy the whole tumor. We believe this work critical to create new therapies that more successfully move from our laboratory models to our human patients.
Wang X, Prager BC, Wu Q, Kim LJY, Gimple RC, Shi Y, Yang K, Morton AR, Zhou W, Zhu Z, Obara EAA, Miller TE, Song A, Lai S, Hubert CG, Jin X, Huang Z, Fang X, Dixit D, Tao W, Zhai K, Chen C, Dong Z, Zhang G, Dombrowski SM, Hamerlik P, Mack SC, Bao S, Rich JN. Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression
Cell Stem Cell. 2018
Mack SC, Pajtler KW, Chavez L, Okonechnikov K, Bertrand KC, Wang X, Erkek S, Federation A, Song A, Lee C, Wang X, McDonald L, Morrow JJ, Saiakhova A, Sin-Chan P, Wu Q, Michaelraj KA, Miller TE, Hubert CG, Ryzhova M, Garzia L, Donovan L, Dombrowski S, Factor DC, Luu B, Valentim CLL, Gimple RC, Morton A, Kim L, Prager BC, Lee JJY, Wu X, Zuccaro J, Thompson Y, Holgado BL, Reimand J, Ke SQ, Tropper A, Lai S, Vijayarajah S, Doan S, Mahadev V, Miñan AF, Gröbner SN, Lienhard M, Zapatka M, Huang Z, Aldape KD, Carcaboso AM, Houghton PJ, Keir ST, Milde T, Witt H, Li Y, Li CJ, Bian XW, Jones DTW, Scott I, Singh SK, Huang A, Dirks PB, Bouffet E, Bradner JE, Ramaswamy V, Jabado N, Rutka JT, Northcott PA, Lupien M, Lichter P, Korshunov A, Scacheri PC, Pfister SM, Kool M, Taylor MD, Rich JN.
Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.
Nature. 2018 Jan 4;553(7686):101-105. doi: 10.1038/nature25169. Epub 2017 Dec 20.
Zhu Z, Gorman M, McKenzie L, Chai J, Hubert CG, Prager B, Fernandez E, Richner J, Zhang R, Shan C, Wang X, Shi PY, Diamond M, Rich JN, and Chheda M.
Zika Virus Has Oncolytic Activity against Glioblastoma Stem Cells.
J Exp Med. 2017 Oct 2;214(10):2843-2857. doi: 10.1084/jem.20171093. Epub 2017 Sep 5.
Wang X, Huang Z, Wu Q, Prager BC, Mack SC, Yang K, Kim LJY, Gimple RC, Shi Y, Lai S, Xie Q, Miller TE, Hubert CG, Song A, Dong Z, Zhou W, Fang X, Zhu Z, Mahadev V, Bao S, Rich JN.
MYC-regulated Mevalonate Metabolism Maintains Brain Tumor Initiating Cells.
Cancer Res. 2017 Jul 20. pii: canres.0114.2017.
Miller TE, Liau BB, Wallace LC, Morton AR, Xie Q, Dixit D, Factor DC, Kim L, Morrow JJ, Wu Q, Mack SC, Hubert CG, Gillespie SM, Flavahan W, Hoffmann T, Thummalapalli R, Hemann MT, Paddison PJ, Horbinski C, Zuber J, Scacheri PC, Bernstein BE, Tesar PJ, Rich JN.
Transcription elongation factors represent in vivo cancer dependencies in glioblastoma.
Nature. 2017 Jul 20;547(7663):355-359
Marcelino Meliso F, Hubert CG, Favoretto Galante PA, Penalva LO.
RNA processing as an alternative route to attack glioblastoma.
Hum Genet. 2017 Sep;136(9):1129-1141. doi: 10.1007/s00439-017-1819-2. Epub 2017 Jun 12. Review.
Jung J, Kim LJY, Wang X, Wu Q, Sanvoranart T, Hubert CG, Prager BC, Wallace LC, Jin X, Mack SC, Rich JN.
Nicotinamide metabolism regulates glioblastoma stem cell maintenance.
JCI Insight. 2017 May 18;2(10). pii: 90019. doi: 10.1172/jci.insight.90019.
Wang X, Yang K, Xie Q, Wu Q, Mack SC, Shi Y, Kim LJ, Prager BC, Flavahan WA, Liu X, Singer M, Hubert CG, Miller TE, Zhou W, Huang Z, Fang X, Regev A, Suvà ML, Hwang TH, Locasale JW, Bao S, Rich JN. Purine synthesis promotes maintenance of brain tumor initiating cells in glioma.
Nat. Neurosci, 2017 May;20(5):661-673. doi: 10.1038/nn.4537.
Ayuso JM, Monge R, Martínez-González A, Virumbrales-Muñoz M, Llamazares GA, Berganzo J, Hernández-Laín A, Santolaria J, Doblaré M, Hubert CG, Rich JN, Sánchez-Gómez P, Pérez-García VM, Ochoa I, Fernández LJ.
Glioblastoma on a microfluidic chip: Generating pseudopalisades and enhancing aggressiveness through blood vessel obstruction events.
Neuro-Onc. 2017 Jan 6. doi: 10.1093/neuonc/now230.
Hubert CG, Rivera M, Spangler LC, Wu Q, Mack SC, Prager BC, Couce M, McLendon RE, Sloan AE, Rich JN. A three-dimensional organoid culture system derived from human glioblastomas recapitulates the hypoxic gradients and cancer stem cell heterogeneity of tumors found in vivo.
Cancer Res. 2016 Feb 19. pii: canres.2402.2015.
- Interviewed by the Journal of the National Cancer Institute, March 2017.
Schonberg DL, Miller TE, Wu Q, Flavahan WA, Das NK, Hale JS, Hubert CG, Mack SC, Jarrar AM, Karl RT, Rosager AM, Nixon AM, Tesar PJ, Hamerlik P, Kristensen BW, Horbinski C, Connor JR, Fox PL, Lathia JD, Rich JN.
Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells.
Cancer Cell. 2015 Oct 12;28(4):441-55. doi: 10.1016/j.ccell.2015.09.002.
Mack SC, Hubert CG, Miller TE, Taylor MD, Rich JN.
An epigenetic gateway to brain tumor cell identity.
Nat Neurosci. 2015 Dec 29;19(1):10-9. doi: 10.1038/nn.4190. Review.
Hitomi M, Deleyrolle LP, Mulkearns-Hubert EE, Jarrar A, Li M, Sinyuk M, Otvos B, Brunet S, Flavahan WA, Hubert CG, Goan W, Hale JS, Alvarado AG, Zhang A, Rohaus M, Oli M, Vedam-Mai V, Fortin JM, Futch HS, Griffith B, Wu Q, Xia CH, Gong X, Ahluwalia MS, Rich JN, Reynolds BA, Lathia JD.
Differential connexin function enhances self-renewal in glioblastoma.
Cell Rep. 2015 May 19;11(7):1031-42. doi: 10.1016/j.celrep.2015.04.021. Epub 2015 May 7.
Xie Q, Wu Q, Mack SC, Yang K, Kim L, Hubert CG, Flavahan WA, Chu C, Bao S, Rich JN.
CDC20 maintains tumor initiating cells.
Oncotarget. 2015 May 30;6(15):13241-54.
Adorno-Cruz V, Kibria G, Liu X, Doherty M, Junk DJ, Guan D, Hubert CG, Venere M, Mulkearns-Hubert E, Sinyuk M, Alvarado A, Caplan AI, Rich JN, Gerson SL, Lathia JD, Liu H.
Cancer Stem Cells: Targeting the Roots of Cancer, Seeds of Metastasis, and Sources of Therapy Resistance.
Cancer Res. 2015 Jan 20. pii: canres.3225.2014.
Hubert CG†, Bradley RK†, Ding Y, Toledo CM, Skutt-Kakaria K, Girard EJ, Davison J, Berndt J, Corrin P, Basom R, Delrow JJ, Webb TR, Pollard SM, Lee JW, Olson JM*, Paddison PJ*
Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. †denotes co-first authors.*denotes co-corresponding authors.
Genes Dev. 2013 May 1;27(9):1032-45. doi: 10.1101/gad.212548.112.
- Profiled in Cancer Discov. News. Published OnlineFirst May 16, 2013; doi: 10.1158/2159-8290.CD-RW2013-105.
Ding Y, Hubert CG, Corrin P, Vazquez J, Baysom R, Zhang B, Risler JK, DeLuca J, Pollard SM, Delrow J, Zhu J, Olson JM, Paddison PJ.
A cancer-specific requirement for BUB1B/BubR1 in human brain tumor isolates and genetically transformed cells.
Cancer Discov. 2012 Feb;3(2):198-211. Epub 2012 Nov 15. PMID: 23154965.
- Commentary in Cancer Discov. 2013 Feb;3(2):141-4. doi: 10.1158/2159-8290.CD-12-0588.
Ou WB, Hubert C, Corson JM, Bueno R, Sugarbaker DJ, Fletcher JA.
Targeted Inhibition of Multiple Receptor Tyrosine Kinases in Mesothelioma.
Neoplasia. 2011 Jan;13(1):12-22.
Jarjour J, West-Foyle H, Certo MT, Hubert CG, Doyle L, Getz MM, Stoddard BL, Scharenberg AM.
High-resolution profiling of homing endonuclease binding and catalytic specificity using yeast surface display.
Nucleic Acids Research. 2009 Sept; doi:10.1093/nar/gkp726.
Hubert CG, McJames S, Mecham I, Dull RO.
Digital Imaging System and Virtual Instrument Platform for Measuring Hydraulic Conductivity of Vascular Endothelial Monolayers.
Microvasc. Res. 2006 Mar; 71(2):135-40.
Dull RO, DeWitt BJ, Dinavahi R, Schwartz L, Hubert C, Pace N, Fronticelli C.
Quantitative assessment of hemoglobin-induced endothelial barrier dysfunction.
J. Appl. Physiol. 2004 Nov; 97(5):1930-7.
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