Experimental Therapeutics and Molecular Imaging Laboratory

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 and 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
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

Research Projects

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

The Tannous laboratory focuses on developing molecular biosensors that report from the tumor 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

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 tag 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

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 cell 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 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. 

Research Positions

Read about and apply for residency, fellowship and observership programs in neurology.

All applicants should register with the Massachusetts General Hospital careers page.

Selected Publications

For a more extensive list of publications, visit PubMed.

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).

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.

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).

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.

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.

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.

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.

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

Bovenberg MS, Degeling MH, Tannous BA. Advances in stem cell therapy against gliomas. Trends Mol Med. 2013;19:281-291.

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.

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.

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

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

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).

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.