Laboratory of Shanta Messerli
|Shanta Messerli, Assistant Research Scientist
Cellular Dynamics Program
|Address||MBL, 7 MBL Street, Woods Hole, MA 02543|
Dr. Messerli’s principal research interests involve examining the signaling mechanisms involved with neuronal injury and repair. This involves studying chemical toxicity and mechanical damage to neurons, possible therapies for neuronal tumors, as well as mechanisms of resistance of tumors to chemotherapeutic drugs. The research program focuses on the development of both effective gene therapy and signal blocking therapeutics to treat a variety of tumors whose growth depends on the kinase PAK1, including those associated with neurofibromatosis type 2 (NF2), gliomas, prostate tumors, and pancreatic cancers. In addition, the laboratory is examining the role of multidrug resistance (MDR) transporters in the development of resistance to chemotherapeutic drugs. A better understanding of the molecular and cellular mechanisms underlying neuronal injury and repair will provide insight into the development of new therapies for neurological diseases.
Current research is investigating the use of anti-cancer therapeutics to treat tumors found in mouse models of neurofibromatosis type 2 (NF2) and neurofibromatosis type I (NF1). NF2 is an autosomal dominant disorder in which patients develop multiple lesions, including meningiomas and gliomas in the brain, and schwannomas, benign tumors of the peripheral nerve sheath, which damage nerves by compression. NF1 is also an autosomal dominantly inherited disorder and is characterized by developmental changes in the nervous system, skin, bones, and other tissues. Its most distinctive features are multiple benign, soft tumors called neurofibromas and patches of skin pigmentation called café-au-lait spots. NF1 can also affect nerves throughout the body, including in the brain and spinal cord.
Gene therapy and /or novel NF therapeutics, may prove to be a complementary strategy to use of chemotherapeutic drugs and neurosurgery for treating these tumors due to the inability of many typical chemotherapeutic drugs to get past the blood brain barrier and the risk of nerve damage with surgery. Our objective is to develop an effective strategy, either using a targeted gene delivery system and/ or by use of a novel anti-cancer therapeutic, which is capable of crossing the blood brain barrier, to reduce growth tumor growth, both in vitro and in NF2 murine models. This work will provide valuable insight into the use of targeted viral vectors and / or novel anti-cancer therapeutics to treat tumors from many forms of cancer. Our broader interests include development and testing of targeted therapies for treatment of a variety of cancers.
*Immortalized human schwannoma HEI-193 cells (House Ear Institute) from a Neurofibromatosis Type 2 (NF2) patient (Hung et al., 1993) imaged with orientation independent differential interference contrast microscopy. These phase contrast images were taken with a 100 x objective (0.3 NA). Scale bar = 10 microns.
(Imaged by Michael Shribak and Shanta Messerli)
Supported by Merrimack Pharmaceuticals, Peterson Foundation, NF CURE, Neurofibromatosis Inc., Yamada Bee Farm, Department of Defense (DOD), NIH, and NSF.
Maruta, H., & Messerli, S. M. (2013). PAK1 in Brain Diseases or Disorders in PAKs, RAC/CDC42 (p21)-activated Kinases. Towards the Cure of Cancer and Other PAK-dependent Diseases, 978-0-12-407198-8, Elsevier, Oxford, UK, pp. 87-106, 10.1016/B978-0-12-407198-8.00005-9.
Maruta, H., Messerli, S. M., & Ramesh, J. (2013). Natural or Synthetic therapeutics that block PAKs in PAKs, RAC/CDC42 (p21)-activated Kinases. Towards the Cure of Cancer and Other PAK-dependent Diseases, ISBN: 978-0-12-407198-8, pp.53-76, 10.1016/B978-0-12-407198-8.00003
Alavian, K. N., Li, H., Collis, L., Bonnanni, L., Zeng, L. Sacchetti, S., Lazrove, E., Nabii, P., Flaherty B., Grahams, M.,Chen, Y., Messerli, S.M., Mariggio, M. A., Rahner, C., McNay,E., Shore, G., Smith, P. J., Hardwick, J. M., & Jonas, E. A. (2011). Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nature Cell Biology, published online 18 September; DOI: 10.1038/ncb2330.
Menachery, A., Graham, D., Messerli, S. M., Pethig, R., & Smith, P. J. S. (2011). Dielectrophoretic tweezer for isolating and manipulating target cells. IET Nanobiotechnology, 5 (1): p. 1-7.
Prabhakar, S., Brenner, G. J, Sung, B., Messerli, S. M., Mao, J., Sena-Esteves, M., Stemmer-Rachamimov, A., Tannous, B., and Breakefield, X.O. (2010). Imaging and therapy of experimental schwannomas using HSV amplicon vector encoding apoptotic protein under Schwann cell promoter. Cancer Gene Therapy, Apr; 17(4): 266-74.
Kasinathan, R. S., Goronga, T., Messerli, S. M., Webb, T. R., & Greenberg, R. M. (2010). Modulation of a Schistosoma mansoni multidrug transporter by the antischistosomal drug praziquantel. FASEB J 24, 128-135.
Maruta, H. & Messerli, S. M. (2010). Development of new anti-cancer drugs that block the kinase PAK1. Frontiers in Drug Design and Discovery, Bentham Books, pp.121-46.
Hashimoto, H.,, Messerli, S. M., Sudo, T.,& Maruta, H. (2009). Ivermectin Inactivates the Kinase PAK1 and Blocks the PAK1-dependent Growth of Human Ovarian Cancer and NF2 Tumor Cell Lines, Drug Discovery and Therapeutics, 3(6): 243-6.
Messerli, S. M., Kasinathan, R. S., Morgan, W., Spranger, S., and Greenberg, R. M. (2009). Schistosoma mansoni P-glycoprotein levels increase in response to praziquantel exposure and correlate with reduced praziquantel susceptibility. Mol Biochem Parasitol, Sept, 167(1) : 54–59.
Messerli, S. M., Ahn, M-R., Kunimasa, K., Yanagihara, M., Tatefuji, T., Hashimoto, K., Mautner, V., Uto, Y., Hori, H., Kumazawa, S., Kaji, K., Ohta, T., & Maruta, H. (2009). Artepillin C (ARC) in Brazilian Green Propolis selectively blocks the oncogenic PAK1 signaling and suppresses the growth of NF tumors in mice. Phytotherapy Research, Mar; 23(3): 423-7.
Demestre, M., Messerli, S. M., Celli, N., Shahhossini, M., Kluwe, L., Mautner, V., & Maruta, H. (2009). CAPE (Caffeic Acid Phenethyl Ester)-based propolis extract (Bio-30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice. Phytotherapy Research, Feb; 23(2): 226-30.
Prabhakar, S., Messerli, S. M., Stemmer-Rachmimov, A., Liu,T., Samuel Rabkin, S., Martuza, R.,and Breakefield,X. O. (2007). Treatment of implantable NF2 schwannoma tumor models with oncolytic herpes simplex virus G47D. Cancer Gene Therapy, 1-8.
Messerli, S. M., Morgan, W, Birkeland, S. R., McArthur, A. G., & Greenberg, R. M. (2006). NO-dependent changes in Schistosoma mansoni gene expression identified by SAGE. Molecular and Biochemical Parasitology, 150: 367-70.
Messerli, S. M. and Greenberg, R. M. (2006). Cnidarian toxins and voltage-gated ion channels. Marine Drugs, 4:70-81.
Messerli, S. M., Prabhakar, S., Tang, Y., Maymood, U., Giovannini, M., Weissleder, R., Bronson, R., Martuza, R., Rabkin, S., & Breakefield, X. O. (2006). Treatment of schwannomas with an oncolytic HSV recombinant virus in murine models of neurofibromatosis type 2. Human Gene Therapy, 17: 1-11.
Stemmer-Rachamimov, A., Louis, D. N., Nielsen, G. P., Antonescu, C., Borowsky, A., Bronson, R., Burns, D.K., Cervera, P., McLaughlin, M., Reifenberger, G., Schmale, M., MacCollin, M., Chao, R., Cichowski, K., Kalamarides, M., Messerli, S. M., McClatchey, A., Niwa-Kawakita, M., Ratner, N., Reilly, K., Zhu, Y. & Giovannini , M. (2004). Comparative pathology of nerve sheath tumors in mouse models and humans. Cancer Research, 64 (10), 3718-3724.
Messerli, S. M., Prabhakar, S., Tang, Y., Shah, K., Cortes, M. L., Murthy, V., Weissleder, R., Breakefield, X. O., & Tung, C. (2004). A novel method for apoptosis imaging an ICE (caspase-1)-near infrared fluorescent imaging probe. Neoplasia, 6 (2): 1-11.
Tang, Y., Shah, K., Messerli, S. M., Snyder, E., Breakefield, X. O., & Weissleder, R. (2003). In vivo tracking of neural progenitor cell migration to glioblastomas. Human Gene Therapy, 14 (13):1247-54.
Messerli, S. M., Tang, Y., Giovannini, M., Bronson, R. T., Weissleder. R. & Breakefield, X. O. (2002). Detection of spontaneous schwannomas by MRI in a transgenic murine model of neurofibromatosis type 2. Neoplasia, 4 (6): 501-509.
Kumar† , S. M., Porterfield, D. M., Muller, K. J., Smith, P. E., & Sahley, C. L. (2001). Nerve Injury induces a rapid efflux of nitric oxide (NO) detected with a novel NO microsensor. The Journal of Neuroscience, 21(1):215-220.
Chen, A.*, Kumar† , S. M.*, Sahley, C. L., & Muller, K. J. (2000). Nitric oxide influences injury- induced microglial migration and accumulation in the leech CNS, The Journal of Neuroscience, 20 (3): 1036-1043. (* designates co-first authors)
Shafer, O. T., Chen, A., Kumar† , S. M., Muller, K. J., & Sahley, C. L. (1998). Injury-induced expression of endothelial nitric oxide synthase by glial and microglial cells in the leech central nervous system within minutes after injury. Proc. R. Soc. Lond. B, 265 (1411): 2171-2175.
Lipton, S. A., Kim, W. K., Choi, Y. B., Kumar† , S., D’Emilia, DM., Rayudu, M.V., Arnelle, D. R., & Stamler, J. S. (1997). Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc. Natl. Acad. Sci. USA, 94(11): 5923-8.
(† Indicates name change from Kumar to Messerli)