Gaussia Princeps

Tannous Lab - Experimental Therapeutics and Molecular Imaging Laboratory

Bakhos Tannous, PhD – Research focus in molecular Imaging, gene transfer technologies and high throughput screening aiming at finding novel therapeutics against brain tumors.

Overview

Gaussia Princeps

Collaborators

 

Affiliations

Overview

The Tannous lab focuses on developing novel imaging, diagnostics and therapeutic strategies for brain tumors. Their work includes: (1) Characterization of the naturally secreted Gaussia luciferase (Gluc) as a blood reporter for monitoring different biological processes including tumor response to therapy, viral infection, circulating stem/neuroprogenitor/T-cells; (2) Engineering different secreted reporters to develop a multiplex high-throughput screening assay to find novel therapeutics against different cancer stem cells state; (3) Developing the concept of metabolic biotinylation of tumor receptors to target imaging and therapeutic agents to brain tumor and to track extracellular vesicles and understand their role in gliomagenesis; (4) Tumor-educated platelets (TEP) for pan-cancer, multi-class detection as well as biomarker discovery and their potential for longitudinal disease monitoring and response to therapy. 

Contact

Neuroscience Center at Massachusetts General Hospital
Massachusetts General Hospital – East
Building 149, 13th Street
Charlestown, MA 02129


Telephone:
617-726-6026

E-mail: 
btannous@hms.harvard.edu
btannous@mgh.harvard.edu 

 

 

 

 

 

 

 

 

 

 

Group Members

Bakhos Tannous, PhD Muscular dystophy research

Principal Investigator

Bakhos A. Tannous, PhD

  • Associate Professor,
    Harvard Medical School
  • Associate Neuroscientist,
    Massachusetts General Hospital
  • Director, Vector Production and
    Development Core

 Research Scientists

Dr. Tannous lab group photo

  • Litia Carvalho, PhD, Post-doctroal Fellow
  • Gulsah Erel, Graduate Student
  • Francesca Favaro, BSC, Graduate Student
  • Evelyn Fitzsimons, Undergraduate Student
  • Renata Fleming, PhD, Post-doctoral Fellow
  • Ghazal Lashgari, MD, Post-doctoral Fellow
  • Danielle Nadira, Student
  • Meghan Robbins, Undergraduate Student
  • Nik Sol, MD, Graduate Student
  • Jihane Tannous, BSc, Research Coordinator
  • Elie Tabet BSc, Graduate Student
  • Jian Teng, Pharm.D, Instructor
  • Tian Tian, PhD, Visiting Scholar
  • Max Zinter, BSc, Research Technician

Alumni Group Members

  • Christian Badr, PhD, Instructor
  • Marco Barazaz, Graduate Student
  • M. Sarah Bovenberg, MD/PhD
  • Sepideh Akbaripanahi, MD, Research student
  • Romain Amante, Graduate Student
  • Latasha Charles, High School Student
  • Kevin Conway, BS, Technician
  • Thijs Crommentuijn, Graduate Student
  • M. Hannah Degeling, MD/PhD
  • Hawasatu Dumbuya, Undergraduate Student
  • Stephanie van Hoppe, Graduate Student
  • Mark de Gooijer, Graduate Student
  • Seyedali Hejazi, MD, Research student
  • Nicola Kahale, Technician
  • Rami Kantar, MD, Post-doctoral Fellow
  • Mariam Kerami, MD/PhD Student
  • Marte Van Keulen, Graduate Student
  • Aleksandar Kirov, BSc, Graduate Student
  • Jorien Koelen
  • Maayke Kuijten
  • Charles Lai, PhD, Instructor
  • Grant Lewandrowski, BS, Technician
  • Casey Maguire, Instructor
  • Mariam Mansour, CURE summer student
  • Danielle Morse, Research Technologist
  • Brenda Ngu, Undergraduate Student
  • Johanna Niers, MD, PhD
  • Mohsen Oleiche, Undergraduate Student
  • Katherine Perry MSc
  • Lisa Pike, MSc.
  • Jessica Pitch, Undergraduate Student
  • Adesina Sanni, MD, Post-doctoral Fellow
  • Adam Stevens, CURE summer student
  • Bing Edna Wang, Undergraduate Student
  • Thomas Wurdinger, PhD

 

 

 

Research Projects

diagram of tumor research

Tumor-Educated platelets in cancer diagnostics and progression

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. We are also unraveling the mechanism by which platelets are educated by the tumor and their role in cancer progression, invasion and metastasis.

Molecular Tumor Biosensors

Gaussia princeps marine copepod imagingBiotin tumor image
Marine copepod
Gaussia Princeps
Targeting tumors with biotin
neuroprogenerator cells Glioblastoma stem cells
Neuroprogenitor cells Glioblastoma stem cells

 

The Tannous laboratory focuses on developing molecular biosensors which reports from tumors environment. Recently, we characterized a novel luciferase from the marine copepod Gaussia princeps (Gaussia luciferase or Gluc) which is the smallest luciferase known (19.9 kDa) and much more sensitive than the ones currently in use. This luciferase is naturally secreted and therefore its expression can be monitored over time by assaying an aliquot of the conditioned medium for its activity. We showed that tumor growth and response to therapy, efficiency of gene transfer as well as stem cell survival and proliferation can be monitored in vivo by assaying few microliters of blood for the Gluc activity. Based on this secreted Gluc, we are currently developing different molecular probes which are activated strictly in the tumor environment and can be monitored both in the blood and/or localized in the animal using in vivo bioluminescence imaging.

Multimodal Imaging in the Context of Cancer

diagram of molecular and imaging concepts

Our laboratory developed the concept of metabolic bioltinylation of mammalian cell surface receptor. By fusing a biotin acceptor peptide (BAP) to a transmembrane domain, we showed that cells in general and tumors in particular tags BAP with a single biotin on the cell surface allowing real-time tracking of cells/tumors with any imaging modalities coupled to streptavidin. This is the first report where a single reporter can be used to track cells in vivo with >5 imaging modalities including bioluminescence, fluorescence, intravital microscopy, magnetic resonance (MR), single photon emission tomography (SPECT) and positron emission tomography (PET). Working with Dr. Ralph Weissleder, we are translating this technology to in vivo applications hoping to achieve more sensitive methods for diagnosis, monitoring of brain tumors and more effective therapeutic modalities which can selectively target brain tumor cells by virtue of biotin-streptavidin system in combination with different therapies. 

 

Novel Gene/Cell/Drug Therapy Against Glioblastoma Stem Cells

High-throughput drug screening process diagram

Our laboratory also focuses on high throughput screening for drugs that act specifically against brain tumor stem-like cells.  We have engineered different secreted reporters which can be multiplexed together to screen for drugs that acts against three different glioma stem cells states, self renewal, differentiation and death.  We have obtained some interesting drug “hits” which we are currently validating in culture as well as in our in vivo primary human invasive brain tumor models.  One of our drug hits is the natural product obtusaquinone, which we found to kill glioma cells and stem cells by inducing high levels of reactive oxygen species. Working with our collaborators Dr. Ralph Mazitschek, a medicinal chemist and Dr. Wilhelm Haas, a proteomics expert, we are developing different analogues of this compound and unraveling the mechanism of action of glioma stem cells death.
 
In another screening project, we found that the family of cardiac glycosides, including lanatoside C, sensitizes glioma and glioma stem cells to the anti-cancer agent TRAIL.  Since TRAIL does not penetrate the brain and therefore brain tumors, we explored the use of viral vectors (AAV vector) and an FDA-approved neural stem cells to deliver TRAIL to gliomas across the blood-brain barrier in combination with lanatoside C. 

We have developed an in vitro model to mimic EMT-like transition in glioblastoma, namely pro-neural-to-mesenchymal transition. Using our multiplexed secreted reporters and shRNA/drug screening combined with proteomics, we are unraveling the mechanism/target that blocks this transition, leading to efficient therapeutic benefit. 

 

Role of Extracellular Vesicles in Glioblastoma Therapy Resistance

gioblastoma therapy

Our laboratory developed the concept of metabolic bioltinylation of mammalian cell surface receptor. By fusing a biotin acceptor peptide (BAP) to a transmembrane domain, we showed that cells in general and tumors in particular tags BAP with a single biotin on the cell surface allowing real-time tracking of cells/tumors with any imaging modalities coupled to streptavidin. This is the first report where a single reporter can be used to track cells in vivo with >5 imaging modalities including bioluminescence, fluorescence, intravital microscopy, magnetic resonance (MR), single photon emission tomography (SPECT) and positron emission tomography (PET). Working with Dr. Ralph Weissleder, we are translating this technology to in vivo applications hoping to achieve more sensitive methods for diagnosis, monitoring of brain tumors and more effective therapeutic modalities which can selectively target brain tumor cells by virtue of biotin-streptavidin system in combination with different therapies.

 

 

 

Research Positions

Read about and apply for residency, fellowship and observership programs at http://www.massgeneral.org/neurology/education/.

All applicants should register with the Mass General Careers Web site at http://www.massgeneral.org/careers/viewall.aspx. Request a list of current open positions at mghneurology@partners.org.

Publications

Our Lab in the News

Chemical and Engineering News
May 2012
Uncovering Cellular Contamination
Assay Development: Glowing enzyme detects mycoplasma hiding in cell culture
By Corinna Wu

Uncovering Cellular Contamination (PDF)

Chemical and Engineering news
News of The Week
Issue Date: May 7, 2012
Spotting Culture Contaminants
Assay Development: Glowing protein detects mycoplasma hiding in cell culture
By Corinna Wu

Spotting Culture Contaminant
(PDF)

Chemical and Engineering News
March 15 2012
Single Gene Allows Scientists To Track Cells In Multiple Ways
Imaging: Cells spotted on MRI, fluorescence imaging, and nuclear-medicine scans
By Katherine Bourzac

Cancer Discovery
April 2012
News in Brief: Reporter Works with Multiple Imaging Types Cancer Discovery April 2012

The scientist
Out, Damned Mycoplasma!
Pointers for keeping your cell cultures free of mycoplasma contamination
By Kelly Rae Chi | December 1, 2013

Selected Publications

  1. Tannous BA, Kim D-E., Fernandez JL, Weissleder RW, and Breakefield, XO. Codon optimized Gaussia luciferase cDNA for mammalian gene expression in culture and in vivo. Mol Therapy 2005;11:435-443 (Journal cover).
  2. Tannous BA., Grimm J, Perry K.F., Chen J., Weissleder R. and Breakefield X.O. Metabolic biotinylation of cell surface receptors for in vivo imaging. Nature Methods 2006;3:391-396.
  3. Wurdinger T, Badr C, Pike L, Badr C, de Klein R, Weissleder R, Breakefield XO, Tannous BA. A secreted luciferase for ex vivo monitoring of in vivo processes Nature Methods 2008;5:171-173 (Journal cover).
  4. 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;14:382-393.
  5. Badr CE, Wurdinger T, Nilsson J, Niers JM, Whalen M, Degterev A and Tannous BA. Lanatoside C sensitizes glioblastoma cells to TRAIL and induces an alternative cell death pathway. Neuro-Oncology, 2011;13:1213-1224.
  6. 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;134:5149-5156.
  7. Badr CE, van hoppe S, Amante R and Tannous BA. Obtusaquinone, a small molecule targeting cancer cells through oxidative stress. J Natl Cancer Inst. 2013;105:643-653.
  8. Tannous BA, Kerami M, Van der Stoop PM, Kwiatkowski N, Wang L, Zhou W, Kessler AF, Lewandrowski G, Hiddingh L, Sol N, Lagerweij T, Wedekind L, Niers JM, Barazas M, Nilsson RJA, Geerts D, De Witt Hamer PC, Hagemann C, Vandertop WP, Van Tellingen O, Noske DP, Gray NS, Wurdinger T. Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to anti-mitotic drugs. J Natl Cancer Inst 2013;105:1322-1331. PMCID: PMC3760778
  9. Bovenberg MS, Degeling MH, Tannous BA. Advances in stem cell therapy against gliomas. Trends Mol Med. 2013;19:281-291.
  10. Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire C, Chen J, *Tannous BA and *Breakefield XO. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 2014;8:483-494. *co-senior authors.
  11. Lai CP, Kim EY, Badr CE, Weissleder R, Mempel TR, Tannous BA*, and Breakefield XO*. Visualization and tracking of tumor extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat Commun, 2015;6:7029. *co-senior authors.
  12. Best M, Sol N, Tannous J, Westerman B, Rustenburg F, Schellen P, Verschueren H, Post E, Koster J, Ylstra Bm Ameziane N, Dorsman J, Smit EF, Verheul HM, Noske DP, Reijneveld JC, Nilsson JA, Tannous BA*, Wesseling P* and Wurdinger T*. RNA-seq of tumor-educated platelets enables blood-based pan-cancer, multiclass and molecular pathway cancer diagnostics. Cancer Cell 2015;28”666-676. * Co-senior authors
  13. Crommentuijn MHW, Kantar R, Noske DP, Vandertop WP, Badr CE, Würdinger T, Maguire CA and Tannous BA. Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model. Mol Ther Oncolytics 2016;3:16017
  14. Crommentuijn MHW, Maguire CA, Niers JM, Vandertop WP, Badr CE, Würdinger T and Tannous BA. Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma. Mol Oncology 2016;10:625-634 (Journal Cover).
  15. Teng J, da Hora CC, Kantar RS, Nakano I, Wakimoto H, Batchelor TT, Chiocca EA, Badr CE and Tannous BA. Dissecting inherent intratumor heterogeneity in patient-derived glioblastoma culture models. Neuro-Oncol, in press.

PubMed Links

NCBI PubMed Publications (Tannous, B)

 

 

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