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Andrei Thomas-Tikhonenko, Ph.D.

Professor of Pathology and Laboratory Medicine
Member, Abramson Cancer Center of the University of Pennsylvania
Member (Associate Member before 2007), Center for Molecular Studies in Digestive and Liver Diseases at the University of Pennsylvania
Associate Professor of Pathology (with tenure), Department of Pathobiology, University of Pennsylvania School of Veterinary 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
BSc (Biochemistry/Virology)
Moscow State University, 1984.
PhD (Oncology/Virology)
Russian Academy of Medical Sciences, 1988.
Post-Graduate Training
Visiting Scientist, Université Libre de Bruxelles, Brussels, Belgium , 1989-1989.
Junior Researcher, Researcher, All-Russia Cancer Research Center, Moscow, Russia, 1989-1990.
Postdoctoral Research Associate, Fred Hutchinson Cancer Research Center, Seattle, WA , 1990-1992.
Staff Scientist, Fred Hutchinson Cancer Research Center, Seattle, WA , 1992-1997.
Permanent link
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Description of Research Expertise

My laboratory has a long-standing interest in pathobiology of solid and hematopoietic malignancies, in particular lymphomas and leukemias and other adult and pediatric cancers driven by MYC overexpression. The current research focuses on the role of non-coding RNAs (including microRNAs) and mRNA processing in cancer pathogenesis and therapeutic resistance.

Description of Research & Rotation Projects
1. The key role of the B-cell receptor (BCR) pathway in lymphoid malignancies
Using novel murine models based on retroviral transduction of bone marrow progenitors, we made a surprising discovery that the resultant neoplasms are prone to losing their B-cell identity and converting into myeloid cancers by virtue of extinguishing the key lineage fidelity transcriptions factor PAX5 (Yu et al, Blood, 2003). Since PAX5 loss entails silencing of key BCR components (e.g., CD19), we were able to address the role of the Pax5-BCR axis in hematological malignancies. We were the first to formally prove that PAX5 promotes neoplastic growth through stimulation of BCR signaling (Cozma et al, J Clin Invest 2007). Subsequently, we made an unexpected discovery that CD19 can drive drives neoplastic growth in the absence of the BCR, by virtue of recruiting PI3 kinase and stabilizing the MYC protein (Chung et al, J Clin Invest 2012). This finding has particular relevance for acute lymphoblastic leukemias derived from immature pro-B-cells. On the other hand, in post-germinal center neoplasms (e.g., diffuse large B-cell lymphoma), activation of MYC by the CD19-BCR complex starts a positive feed-forward loop, whereby MYC boosts BCR signaling by down-modulating its antagonists known as ITIM proteins (Psathas et al, Blood 2013).

2. microRNAs as key downstream effectors of MYC
Our interest in non-canonical functions of MYC was spurred by the early discovery that some of well-known MYC-repressed genes (e.g., the angiogenesis inhibitor thrombospondin-1) are regulated by MYC at the level of mRNA turnover, not promoter silencing (Janz et al, Nucl Acids Res 2000). At the time, we didn’t know what the underlying mechanism was, but the discovery of the first MYC-activated microRNA cluster, miR-17-92 (a.k.a. oncomir-1) provided us with an intriguing clue. We indeed discovered that thrombospondin-1 is an essential target of the MYC - miR-17-92 axis, and that this targeting drives tumor angiogenesis (Dews et al, Nat Genet 2006). This was the first demonstration of microRNAs affecting tumor microenvironment – and the second report of microRNAs playing a role in gene repression by MYC. Subsequently, we showed, in collaboration with the Mendell and Dang labs, that MYC also down-regulates select microRNA leading to a broad gene activation program (Chang et al, Nat Genet 2008). The mechanisms of microRNA deregulation by MYC range from promoter-based to biogenesis-mediated. For example, we found that MYC regulates Lin28b, which is a key negative regulator of the let-7 family of tumor suppressive microRNAs (Chang et al, Proc Natl Acad Sci USA 2009).

3. Harnessing the pro-apoptotic acitivity of Myc for therapeutic purposes
While Myc is a gene known to drive tumor cell proliferation, it also accounts for high levels of cell death, and in certain types of B-lymphomas the so-called MYC signature correlates with improved survival. The unmet challenge is to boost the pro-apoptotic effects of Myc without promoting growth of neoplastic cells. We had begun to address this challenge by refining our murine B-cell neoplasm models to include conditional activation of MYC (Yu et al, Cancer Res 2005) or transient reactivation of the p53 tumor suppressor (Yu et al, Blood 2007; Amaravadi et al, J Clin Invest 2007). Subsequently, we demonstrated that the increase in therapeutic apoptosis could be achieved by inhibiting microRNAs that target endogenous MYC such as miR-34a (Sotillo et al, Oncogene 2011). We are currently pursuing the idea that chemosensitization could be achieved pharmacologically by transiently elevating MYC levels with small-molecules inhibitors of GSK3.

4. Understanding and targeting tumor angiogenesis
This work had begun in earnest with the discovery that Myc overexpression is necessary for the hyper-vascular phenotype in simple xenograft models (Ngo et al, Cell Growth Diff, 2000) as well as in genetically complex cancers. This frequently occurs by a microRNA-dependent mechanism, through activation of the miR-17-92 cluster (see above). Subsequently, we demonstrated that in solid tumors, such as pediatric neuroblastoma and colon adenocarcinoma, deregulation of miR-17-92 leads to profound suppression of TGFβ signaling and diminished production of many anti-angiogenic TGFβ-inducible factors such as thrombospondin-1, CTGF, and clusterin (Dews et al, Cancer Res 2010). In fact, the MYC | miR-1792 and TGFβ pathways exhibit an epistatic relationship, where mutations in one pathway make mutations in the other redundant (Dews et al, J Natl Cancer Inst 2014). However, miR-17-92 is not the only pro-angiogenic microRNA. For example, colon cancer neovascularization also requires p53-regulated miR-194 (Sundaram et al, Cancer Res 2011). Thus, targeting microRNAs might be a viable anti-angiogenic strategy, especially in tumors without VEGF overexpression.

Lab personnel:
Elena Sotillo, PhD, Scientist III
Danika Johnston, PhD, Research Associate
Asen Bagashev, PhD, Postdoctoral Fellow
Katy Black, PhD, Postdoctoral Fellow
Elisabeth Gillespie, PhD, Postdoctoral Fellow
Ammar Naqvi, PhD, Postdoctoral Fellow in Bioinformatics (jointly with DBHi)
Colleen Harrington, CAMB Graduate Student
Claudia Lanauze, CAMB Graduate Student
Suzanna Talento, Research Technician
Antonio Muscarella, Penn Undergraduate Student
Marcela Robaina, Visiting Scientist (INCA, Rio de Janeiro, Brazil)
Daniel Soto De Jesus, CAMB Graduate Student (Fall '15 rotation)
Kathryn Wurges, MHA/MHE, Resource Coordinator II

Selected Publications

E.Sotillo, D.M.Barrett, K.L.Black, A.Bagashev, D.Oldridge, G.Wu, R.Sussman, C.Lanauze, M.Ruella, M.R.Gazzara, N.M.Martinez, C.T.Harrington, E.Y.Chung, J.Perazzelli, T.J.Hofmann, S.L.Maude, P.Raman, A.Barrera, S.Gill, S.F.Lacey, J.J.Melenhorst, D.Allman, E.Jacoby, T.Fry, C.Mackall, Y.Barash, K.W.Lynch, J.M.Maris, S.A.Grupp, and Andrei Thomas-Tikhonenko: Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov 5(12), December 2015 Notes: EDITORS' CHOICE: S. Behjati "Hiding from the enemy", Science Translational Medicine, 7 (313), 313ec193 (2015); RESEARCH HIGHLIGHT: G.K.Alderton "Skipping out epitopes", Nature Reviews Cancer, 15, 699 (2015).

J.N.Psathas and A.Thomas-Tikhonenko: MYC and the art of microRNA maintenance. Cold Spring Harb Perspect Med 4(8): a014175, 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.

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Last updated: 11/25/2015
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