Andrei Thomas-Tikhonenko, Ph.D.

faculty photo
Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
Colket Translational Research Bldg, Rm 4056
3501 Civic Center Blvd
Philadelphia, PA 19104
Office: 267-426-9699
Fax: 267-426-8125
Education:
BSc (Biochemistry/Virology)
Moscow State University, 1984.
PhD (Oncology/Virology)
Russian Academy of Medical Sciences, 1988.
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Description of Research Expertise

Research Interests
c-Myc, N-Myc, and other nuclear oncoproteins; Pax5, B-cell receptor signaling, and B-cell differentiation; microRNAs and cancer; tumor microenvironment; hematological malignancies, pediatric cancers.

Key words: Myc, p53, microRNAs, angiogenesis, colon cancer, B-lymphoma, neuroblastoma

Description of Research
Our laboratory is broadly interested in the mechanisms of neoplastic transformation by the Myc family oncoproteins (including c- and N-Myc), in particular Myc-regulated non-coding microRNAs. To determine the contribution of Myc to malignant growth in hematopoietic tissues, we have developed a new mouse model for B-cell lymphoma based on infection of p53-null bone marrow progenitors by a Myc-encoding retrovirus (Yu et al, Blood 2007; Cozma et al, J Clin Invest 2007). In this system, the salient features of Myc-induced lymphomagenesis are overexpression of the oncogenic miR-17-92 microRNA cluster and simultaneous repression of several tumor suppressive microRNAs, such as miR-15/16, miR-34, and let-7 (Chang et al, Nature Genet 2008; Chung et al, Cancer Biol Ther 2008; Chang et al, Proc Natl Acad Sci 2009). These microRNAs help sustain c-Myc levels and contribute to deregulation of multiple Myc target genes, B-cell receptor signaling, and therapeutic apoptosis. In solid tumors, such as pediatric neuroblastoma and colon adenocarcinoma, deregulation of miR-17-92 leads to profound suppression of TGFbeta signaling and sharply diminished production of many anti-angiogenic factors such as thrombospondin-1 and clusterin (Dews et al, Nature Genet 2006; Chayka et al, J Natl Cancer Inst 2009). This brings about robust tumor neovascularization and enhanced neoplastic growth. Our studies highlight the key roles of microRNAs in gene regulation by oncogenic transcription factors in both solid and hematological malignancies.

Rotation Projects for 2009-2010

1. The interplay between Myc, p53, and Pax5 in B-lymphomagenesis. We are primarily interested in elucidating how Myc- and Pax5 deregulated microRNAs, such as miR-15/16 and miR-34, affect B-cell receptor signaling (which leads to cell proliferation) and the p53 pathway (which mediates therapeutic apoptosis.)
2. Regulation of the thrombospondin-1 and related anti-angiogenic factors by a microRNA-based mechanism. The focus of this project is on the miR-17-92 microRNA cluster and how it affects TGFbeta signaling and its downsteam effectors, e.g. thrombospondin superfamily proteins. Both murine and zebrafish-based models are used to address the role of angiogenesis in tumor growth.
3. The contribution of microRNAs to gene regulation by oncogenic transcription factors. Our preliminary data indicate that many well-known Myc target genes are regulated by a microRNA-mediated, not direct DNA binding-based mechanism. We aim to determine to what extent global down-regulation of microRNA biogenesis would compromise the function of the Myc family members.
4. Molecular analysis of somatic mutations in 3’ untranslated regions (3’UTR). Recent data from various cancer genome sequencing projects have revealed the abundance of mutations that affect non-protein-coding segments of many cancer-related genes. Our hypothesis is that mutations in 3’UTR affect regulation by microRNAs and thus provide an epigenetic mechanism for gene overexpression or silencing.

Lab personnel:

Michael Dews, PhD, Senior Scientist
Elena Sotillo, PhD, Scientist
Danika Johnston, PhD, Research Associate,
Grace Tan, PhD, Postdoctoral Fellow
Asen Bagashev, PhD, Postdoctoral Fellow
Colleen Harrington, CAMB Rotating Graduate Student (Fall '13)
Pichai Raman, Bioinformatician (part-time)
Kathryn Wurges, MHA/MHE, Resource Coordinator

Selected Publications

J.N.Psathas and A.Thomas-Tikhonenko: MYC and the art of microRNA maintenance. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a014175- April 2014.

M.Dews, G.S.Tan, S.Hultine, P.Raman, J.Choi, E.K.Duperret, J.Lawler, A.Bass, and A.Thomas-Tikhonenko: Masking epistasis between MYC and TGFβ pathways in anti-angiogenesis mediated colon cancer suppression. J Natl Cancer Inst 106(4): dju043, April 2014.

J.N.Psathas, P.J.Doonan, P.Raman, B.D.Freedman, A.J.Minn, and A.Thomas-Tikhonenko: The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop. Blood 122(26): 4220-4229, Dec 2013.

J.L.Fox, M.Dews, A.J.Minn, A.Thomas-Tikhonenko: Targeting of TGFβ signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma. RNA 19(2): 177-190, Feb 2013.

E.Y.Chung, J.N.Psathas, D.Yu, Y.Li, M.J.Weiss, and A.Thomas-Tikhonenko: CD19 is a major B-cell receptor-independent activator of Myc-driven B-lymphomagenesis. J Clin Invest 122(6): 2257-2266, June 2012.

P.Sundaram , S.Hultine, L.M.Smith, M.Dews, J.L.Fox, D.Biyashev, J.M.Schelter, Q.Huang, M.A.Cleary, O.V.Volpert, A.Thomas-Tikhonenko: p53-responsive miR-194 inhibits thrombospondin-1 and promotes angiogenesis in colon cancers. Cancer Res 71(24): 7490-7501, Dec 2011.

E.Sotillo and A.Thomas-Tikhonenko: The long reach of non-coding RNAs. Nature Genet 43(7): 616-617, July 2011 Notes: Nature Genetics TOP CONTENT, July 2011.

E.Sotillo, T.Laver, H.Mellert, J.M.Schelter, M.A.Cleary, S.McMahon, A.Thomas-Tikhonenko: Myc overexpression brings out unexpected anti-apoptotic effects of miR-34a. Oncogene 30(22): 2587–2594, June 2011 Notes: Oncogene TOP TEN list, June 2011.

M.Dews, J.Fox, S.Hultine, P.Sundaram, W.Wang, Y.Y.Liu, E.Furth, G.H.Enders, W.El-Deiry, J.M.Schelter, M.A.Cleary, A.Thomas-Tikhonenko: Myc - miR-17~92 axis blunts TGFβ signaling and production of multiple TGFβ-dependent anti-angiogenic factors. Cancer Res 70(20): 8233-8246, Oct 2010.

P.Mestdagh, A.K.Boström, F.Impens, E.Fredlund, G.Van Peer, P.De Antonellis, K. von Stedingk, B.Ghesquière, S.Schulte, M.Dews, A.Thomas-Tikhonenko, J.H. Schulte, M.Zollo, A.Schramm, K.Gevaert, H.Axelson, F.Speleman, and J.Vandesompele: Protein profiling identifies miR-17-92 as a master regulator of TGFβ-pathway activity in neuroblastoma. Mol Cell 40(5): 762–773, Dec 2010.

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Last updated: 04/18/2014
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