Photo of Bakhos A. Tannous,  PhD

Bakhos A. Tannous, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-6026
Fax: (617) 724-1537


btannous@hms.harvard.edu

Bakhos A. Tannous, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Associate Professor, Neurology, Harvard Medical School
  • Associate Neuroscientist, Neurology, Massachusetts General Hospital
  • Director, Interdepartmental Neuroscience Center, Neurology, Massachusetts General Hospital
  • Co-Director, Molecular Neurogenetics Unit-East, Neurology, Massachusetts General Hospital
  • Director, MGH Viral Vector Development Facility, Neurology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Glioblastomas (GBMs) comprises >50% of all primary brain tumors and are the most malignant type with a 5-year survival rate of only 3.3%, despite standard-of-care (radiation, and temozolomide). Recently it has been shown that the majority of GBM cells do not have the capacity to recapitulate a phenocopy of the original tumor and that it is only a small subpopulation of glioma stem-like cells (GSCs; or tumor initiating cells) in the tumor have that this ability upon xenotransplantation in nude mice. These GSCs are known to be resistant to therapy and are thought to be largely responsive for tumor recurrence and patient death, thus providing a clinically-relevant model to study GBM. GBMs are highly heterogeneous and there is a complex interaction among different subtypes of tumor cells and stromal cells associated with the tumor which can modify the tumor itself as well as its microenvironment to promote tumor growth, invasion, angiogenesis and immune suppression. The transcriptome profiles of GBMs has identified four major subtypes, two of which, proneural (PN) and mesenchymal (MES), predominate. Further, single cell RNA sequencing has revealed that multiple GBM subtypes can reside within the same tumor. GBM with enriched MES properties typically display a more aggressive phenotype both in vitro and in vivo with pronounced radio/chemo resistance.

One aspect our work is to to screen for drugs which can increase therapeutic efficacy for GBM stem cells by either: (1) eradicating these cells; (2) revert GSCs into a more differentiated state which can then response to conventional therapies; (3) sensitizing GSCs to temozolomide; and (4) inhibit PMT in GSCs. We do this using state-of-the-art multiplex secreted bioluminescent reporters which we have developed and optimized for high-throughput screening as well as in vivo imaging to monitor these processes non-invasively.

Another aspect of our work is unravel the role of extracellular vesicles in GBM progression. Tumor cells have an insidious, “Trojan horse”-like mechanism to manipulate other tumor cells or normal cells in their environment using tumor-derived extracellular vesicles (tEVs). These vesicles, which are produced in abundance by tumor cells, contain both a representation and an enriched subset of cellular proteins and RNAs which can subvert the phenotype of recipient cells, including the normal cells in the tumor environs, as well as other tumor cells. While EVs can serve a normal function in cell-to-cell communication and elimination of proteins and RNAs from cells, tEVs effectively “hijack” this process to promote oncogenicity. Our goal is to understand the role of tEV in PMT phenotypic switch and immune suppression using different tEV-specific fluorescent and bioluminescent reporters which we have developed.

Working with our long-time collaborator Dr. Thomas Würdinger, we showed for the first time that blood platelets carry tumor-derived biomarkers and specific gene signatures that can distinguish patients with localized and metastasized tumors from healthy individuals. We called this phenomena tumor-educated platelets or TEP. We are currently evaluating TEP for pan-cancer, multi-class detection as well as biomarker discovery and their potential for longitudinal disease monitoring and response to therapy.

 

Publications

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  • Best MG, Sol N, Tannous BA, Wesseling P, Wurdinger T. Re: a Word of Caution on New and Revolutionary Diagnostic Tests. Cancer Cell 2016; 29:143-4. PubMed
  • Crommentuijn MH, Maguire CA, Niers JM, Vandertop WP, Badr CE, Würdinger T, Tannous BA. Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma. Mol Oncol 2015. PubMed
  • Best MG, Sol N, Kooi I, Tannous J, Westerman BA, Rustenburg F, Schellen P, Verschueren H, Post E, Koster J, Ylstra B, Ameziane N, Dorsman J, Smit EF, Verheul HM, Noske DP, Reijneveld JC, Nilsson RJ, Tannous BA, Wesseling P, Wurdinger T. RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics. Cancer Cell 2015; 28:666-76. PubMed
  • Wong HK, Fatimy RE, Onodera C, Wei Z, Yi M, Mohan A, Gowrisankaran S, Karmali P, Marcusson E, Wakimoto H, Stephens R, Uhlmann EJ, Song JS, Tannous B, Krichevsky AM. The Cancer Genome Atlas Analysis Predicts MicroRNA for Targeting Cancer Growth and Vascularization in Glioblastoma. Mol Ther 2015. PubMed
  • Balaj L, Atai NA, Chen W, Mu D, Tannous BA, Breakefield XO, Skog J, Maguire CA. Heparin affinity purification of extracellular vesicles. Sci Rep 2015; 5:10266. PubMed
  • Lai CP, Kim EY, Badr CE, Weissleder R, Mempel TR, Tannous BA, Breakefield XO. Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat Commun 2015; 6:7029. PubMed
  • Kuijten MM, Hannah Degeling M, Chen JW, Wojtkiewicz G, Waterman P, Weissleder R, Azzi J, Nicolay K, Tannous BA. Multimodal targeted high relaxivity thermosensitive liposome for in vivo imaging. Sci Rep 2015; 5:17220. PubMed
  • Teng J, Hejazi S, Badr CE, Tannous BA. Systemic anticancer neural stem cells in combination with a cardiac glycoside for glioblastoma therapy. Stem Cells 2014. PubMed
  • Hiddingh L, Tannous BA, Teng J, Tops B, Jeuken J, Hulleman E, Boots-Sprenger SH, Vandertop WP, Noske DP, Kaspers GJ, Wesseling P, Wurdinger T. EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma. 2014; 5:363-74. PubMed
  • Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire CA, Chen JW, Tannous BA, Breakefield XO. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 2014; 8:483-94. PubMed
  • Elman JS, Murray RC, Murray RM, Wang F, Shen K, Gao S, Conway KE, Yarmush ML, Tannous BA, Weissleder R, Parekkadan B. Pharmacokinetics of natural and engineered secreted factors delivered by mesenchymal stromal cells. PLoS ONE 2014; 9:e89882. PubMed
  • Lai CP, Tannous BA, Breakefield XO. Noninvasive in vivo monitoring of extracellular vesicles. Methods Mol Biol 2013; 1098:249-58. PubMed
  • Lewandrowski GK, Magee CN, Mounayar M, Tannous BA, Azzi J. Simultaneous in vivo monitoring of regulatory and effector T lymphocytes using secreted Gaussia luciferase, Firefly luciferase, and secreted alkaline phosphatase. Methods Mol Biol 2013; 1098:211-27. PubMed
  • van der Mijn JC, Sol N, Mellema W, Jimenez CR, Piersma SR, Dekker H, Schutte LM, Smit EF, Broxterman HJ, Skog J, Tannous BA, Wurdinger T, Verheul HM. Analysis of AKT and ERK1/2 protein kinases in extracellular vesicles isolated from blood of patients with cancer. J Extracell Vesicles 2014; 3:25657. PubMed
  • Bovenberg MS, Degeling MH, Hejazi S, Amante RJ, van Keulen M, Jeuken JW, Akbaripanahi S, Vleggeert-Lankamp CL, Tannous M, Wesseling P, Wurdinger T, Tannous BA. Multiplex blood reporters for simultaneous monitoring of cellular processes. Anal Chem 2013; 85:10205-10. PubMed
  • Tannous BA, Kerami M, Van der Stoop PM, Kwiatkowski N, Wang J, Zhou W, Kessler AF, Lewandrowski G, Hiddingh L, Sol N, Lagerweij T, Wedekind L, Niers JM, Barazas M, Nilsson RJ, Geerts D, De Witt Hamer PC, Hagemann C, Vandertop WP, Van Tellingen O, Noske DP, Gray NS, Würdinger T. Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs. Journal of the National Cancer Institute 2013; 105:1322-31. PubMed
  • Bovenberg MS, Degeling MH, Tannous BA. Cell-based immunotherapy against gliomas: from bench to bedside. Mol Ther 2013. PubMed
  • Bovenberg MS, Degeling MH, Tannous BA. Advances in stem cell therapy against gliomas. Trends Mol Med 2013. PubMed
  • Badr CE, Van Hoppe S, Dumbuya H, Tjon-Kon-Fat LA, Tannous BA. Targeting cancer cells with the natural compound obtusaquinone. Journal of the National Cancer Institute 2013. PubMed
  • Maguire CA, Bovenberg MS, Crommentuijn MH, Niers JM, Kerami M, Teng J, Sena-Esteves M, Badr CE, Tannous BA. Triple bioluminescence imaging for in vivo monitoring of cellular processes. Mol Ther Nucleic Acids 2013; 2:e99. PubMed
  • van Rijn S, Nilsson J, Noske DP, Vandertop WP, Tannous BA, Würdinger T. Functional multiplex reporter assay using tagged Gaussia luciferase. Sci Rep 2013; 3:1046. PubMed
  • Kodack DP, Chung E, Yamashita H, Incio J, Duyverman AM, Song Y, Farrar CT, Huang Y, Ager E, Kamoun W, Goel S, Snuderl M, Lussiez A, Hiddingh L, Mahmood S, Tannous BA, Eichler AF, Fukumura D, Engelman JA, Jain RK. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc Natl Acad Sci U S A 2012; 109:E3119-27. PubMed
  • Niers JM, Chen JW, Lewandrowski G, Kerami M, Garanger E, Wojtkiewicz G, Waterman P, Keliher E, Weissleder R, Tannous BA. Single reporter for targeted multimodal in vivo imaging. J Am Chem Soc 2012; 134:5149-56. PubMed
  • Badr CE, Tannous BA. Bioluminescence imaging: progress and applications. Trends Biotechnol 2011. PubMed
  • Badr CE, Wurdinger T, Nilsson J, Niers JM, Whalen M, Degterev A, Tannous BA. Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and induces an alternative cell death pathway. 2011. PubMed
  • Tannous BA, Teng J. Secreted blood reporters: insights and applications. Biotechnol Adv 2011; 29:997-1003. PubMed
  • Niers JM, Kerami M, Pike L, Lewandrowski G, Tannous BA. Multimodal in vivo imaging and blood monitoring of intrinsic and extrinsic apoptosis. Mol Ther 2011. PubMed
  • Niers JM, Chen JW, Weissleder R, Tannous BA. Enhanced in vivo imaging of metabolically biotinylated cell surface reporters. Anal Chem 2011; 83:994-9. PubMed
  • Smits M, Mir SE, Nilsson RJ, van der Stoop PM, Niers JM, Marquez VE, Cloos J, Breakefield XO, Krichevsky AM, Noske DP, Tannous BA, Würdinger T. Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2. PLoS ONE 2011; 6:e16282. PubMed
  • Badr CE, Wurdinger T, Tannous BA. Functional Drug Screening Assay Reveals Potential Glioma Therapeutics. 2010. PubMed
  • Smits M, Nilsson J, Mir SE, van der Stoop PM, Hulleman E, Niers JM, de Witt Hamer PC, Marquez VE, Cloos J, Krichevsky AM, Noske DP, Tannous BA, Würdinger T. miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. 2011; 1:710-20. PubMed
  • Mir SE, De Witt Hamer PC, Krawczyk PM, Balaj L, Claes A, Niers JM, Van Tilborg AA, Zwinderman AH, Geerts D, Kaspers GJ, Peter Vandertop W, Cloos J, Tannous BA, Wesseling P, Aten JA, Noske DP, Van Noorden CJ, Würdinger T. In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell 2010; 18:244-57. PubMed
  • Prabhakar S, Brenner GJ, Sung B, Messerli SM, Mao J, Sena-Esteves M, Stemmer-Rachamimov A, Tannous B, Breakefield XO. Imaging and therapy of experimental schwannomas using HSV amplicon vector-encoding apoptotic protein under Schwann cell promoter. Cancer Gene Ther 2010; 17:266-74. PubMed
  • Sharma R, Tsuchiya M, Skobe Z, Tannous BA, Bartlett JD. The acid test of fluoride: how pH modulates toxicity. PLoS ONE 2010; 5:e10895. PubMed
  • Saydam O, Shen Y, Würdinger T, Senol O, Boke E, James MF, Tannous BA, Stemmer-Rachamimov AO, Yi M, Stephens RM, Fraefel C, Gusella JF, Krichevsky AM, Breakefield XO. Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway. Mol Cell Biol 2009; 29:5923-40. PubMed
  • Maguire CA, Deliolanis NC, Pike L, Niers JM, Tjon-Kon-Fat LA, Sena-Esteves M, Tannous BA. Gaussia luciferase variant for high-throughput functional screening applications. Anal Chem 2010; 81:7102-6. PubMed
  • Tannous BA,Christensen AP,Pike L,Wurdinger T,Perry KF,Saydam O,Jacobs AH,Garcia-Anoveros J,Weissleder R,Sena-Esteves M,Corey DP,Breakefield XO. Mutant sodium channel for tumor therapy. Mol Ther 2009; 17:810-9. PubMed
  • Würdinger T, Tannous BA. Glioma angiogenesis: Towards novel RNA therapeutics. Cell Adh Migr 2009; 3:230-5. PubMed
  • Tannous B, Lee-Lewandrowski E, Sharples C, Brugge W, Bigatello L, Thompson T, Benzer T, Lewandrowski K. Comparison of conventional guaiac to four immunochemical methods for fecal occult blood testing: implications for clinical practice in hospital and outpatient settings. Clin Chim Acta 2009; 400:120-2. PubMed
  • van Vuurden DG, Yazdani M, Bosma I, Broekhuizen AJ, Postma TJ, Heimans JJ, van der Valk P, Aronica E, Tannous BA, Würdinger T, Kaspers GJ, Cloos J. Attenuated AMPA receptor expression allows glioblastoma cell survival in glutamate-rich environment. PLoS ONE 2009; 4:e5953. PubMed
  • Tannous BA. Gaussia luciferase reporter assay for monitoring biological processes in culture and in vivo. Nat Protoc 2009; 4:582-91. PubMed
  • Chung E, Yamashita H, Au P, Tannous BA, Fukumura D, Jain RK. Secreted Gaussia luciferase as a biomarker for monitoring tumor progression and treatment response of systemic metastases. PLoS ONE 2009; 4:e8316. PubMed
  • Wurdinger T,Tannous BA,Saydam O,Skog J,Grau S,Soutschek J,Weissleder R,Breakefield XO,Krichevsky AM. miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell 2008; 14:382-93. PubMed
  • Deliolanis NC,Kasmieh R,Wurdinger T,Tannous BA,Shah K,Ntziachristos V. Performance of the red-shifted fluorescent proteins in deep-tissue molecular imaging applications. J Biomed Opt 2008; 13:044008. PubMed
  • Hewett JW, Nery FC, Niland B, Ge P, Tan P, Hadwiger P, Tannous BA, Sah DW, Breakefield XO. siRNA knock-down of mutant torsinA restores processing through secretory pathway in DYT1 dystonia cells. Hum Mol Genet 2008; 17:1436-45. PubMed
  • Lewandrowski K, Flood J, Finn C, Tannous B, Farris AB, Benzer TI, Lee-Lewandrowski E. Implementation of point-of-care rapid urine testing for drugs of abuse in the emergency department of an academic medical center: impact on test utilization and ED length of stay. Am J Clin Pathol 2008; 129:796-801. PubMed
  • Wurdinger T,Badr C,Pike L,de Kleine R,Weissleder R,Breakefield XO,Tannous BA. A secreted luciferase for ex vivo monitoring of in vivo processes. Nat Methods 2008; 5:171-3. PubMed
  • Hewett JW, Tannous B, Niland BP, Nery FC, Zeng J, Li Y, Breakefield XO. Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells. Proc Natl Acad Sci U S A 2007; 104:7271-6. PubMed
  • Badr CE, Hewett JW, Breakefield XO, Tannous BA. A highly sensitive assay for monitoring the secretory pathway and ER stress. PLoS ONE 2007; 2:e571. PubMed
  • Tannous BA, Grimm J, Perry KF, Chen JW, Weissleder R, Breakefield XO. Metabolic biotinylation of cell surface receptors for in vivo imaging. Nat Methods 2006; 3:391-6. PubMed
  • Tannous BA, Kim DE, Fernandez JL, Weissleder R, Breakefield XO. Codon-optimized Gaussia luciferase cDNA for mammalian gene expression in culture and in vivo. Mol Ther 2005; 11:435-43. PubMed
  • Deliolanis NC, Dunham J, Wurdinger T, Figueiredo JL, Bakhos T, Ntziachristos V. In-vivo imaging of murine tumors using complete-angle projection fluorescence molecular tomography. J Biomed Opt 2009; 14:030509. PubMed
  • Lee-Lewandrowski E, Januzzi JL, Green SM, Tannous B, Wu AH, Smith A, Wong A, Murakami MM, Kaczmarek J, Apple FS, Miller WL, Hartman K, Jaffe AS. Multi-center validation of the Response Biomedical Corporation RAMP NT-proBNP assay with comparison to the Roche Diagnostics GmbH Elecsys proBNP assay. Clin Chim Acta 2007; 386:20-4. PubMed
  • Badr CE, Niers JM, Tjon-Kon-Fat LA, Noske DP, Wurdinger T, Tannous BA. Real-time monitoring of nuclear factor kappaB activity in cultured cells and in animal models. Mol Imaging 2009; 8:278-90. PubMed
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