Andrei
  
Thomas-Tikhonenko
Ph.D.
Email: 
andreit@email.chop.edu
Address: 
Colket Translational Research Bldg, Rm 4056 3501 Civic Center Blvd
267-426-9699
Affiliations
Expertise

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 several mouse models for B-cell lymphoma based on infection of p53-deficient bone marrow progenitors by a Myc-encoding retrovirus. Using this and other systems, we discovered that 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. These microRNAs help sustain c-Myc levels and contribute to deregulation of multiple Myc target genes, B-cell receptor signaling, and therapeutic apoptosis. Additionally, deregulation of miR-17-92 leads to profound suppression of TGFbeta signaling which is important for both normal lymphocyte development and tumor angiogenesis.

Our laboratory is broadly interested in the mechanisms of neoplastic transformation by Myc oncoprotein-regulated microRNAs. To determine the contribution of Myc to malignant growth in hematopoietic tissues, we have developed a new mouse model for B-cell lymphoma. 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. These microRNAs help sustain c-Myc levels and contribute to deregulation of B-cell receptor signaling, and therapeutic apoptosis. Additionally, in solid tumors such as pediatric neuroblastoma, glioblastoma, and colon adenocarcinoma, deregulation of miR-17-92 leads to profound suppression of TGFß signaling and sharply diminished production of many anti-angiogenic factors such as thrombospondin-1 and clusterin. We are currently pursuing the idea that targeting cancer-associated microRNA could be an effective therapeutic strategy.

The Thomas-Tikhonenko laboratory is currently composed of two research scientists, three postdoctoral fellows, and two graduate students. Four past trainees hold faculty positions at Temple University in Philadelphia, PA, Eastern Nazarene College in Quincy, MA, and Yangzhou and Southwest Jiaotong Universities in China. Other trainees currently pursue or have recently completed residency training at Brigham and Women's Hospital, Boston University Medical Center, Bronx Lebanon Hospital, and Hospital of the University of Pennsylvania.

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
Elaine Chung, PhD, Postdoctoral Researcher
James Psathas, PhD, Postdoctoral Researcher
Grace Tan, PhD, Postdoctoral Researcher
Colleen Harrington, CAMB Rotating Graduate Student
Pichai Raman, Bioinformatician (part-time)
Kathryn Wurges, MHA/MHE, Resource Coordinator

Appointments
Associate Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2008 – 2013)
Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2013– present)
Education
PhD, Oncology/Virology, Russian Academy of Medical Sciences (1988)
BSc, Biochemistry/Virology, Moscow State University (1984)
Selected Publications
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. Vol 122(26) . 2013 Dec:4220-4229.
J.L.Fox, M.Dews, A.J.Minn, A.Thomas-Tikhonenko. Targeting of TGFß signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma. RNA. Vol 19(2) . 2013 Feb:177-190.
L.S.Hart, J.T.Cunningham, T.Datta, S.Dey, F.Tameire, S.L.Lehman, B.Qiu, H.Zhang, G.Cerniglia, M.Bi, Y.Li, Y.Gao, H.Liu, C.Li, A.Maity, A.Thomas-Tikhonenko, A.E.Perl, A.Koong, S.Y.Fuchs, J.A.Diehl, I.G.Mills, D.Ruggero, and C.Koumenis. Endoplasmic Reticulum Stress-Mediated Autophagy Promotes Myc-Dependent Transformation and Tumor Growth. J Clin Invest. Vol 122(12) . 2012 Dec:4621-4634.
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. Vol 122(6) . 2012 June:2257-2266.
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. Vol 71(24) . 2011 Dec:7490-7501.
E.Sotillo and A.Thomas-Tikhonenko. The long reach of non-coding RNAs. Nature Genet. Vol 43(7) . 2011 July:616-617.
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. Vol 30(22) . 2011 June:2587?2594.
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 TGFß signaling and production of multiple TGFß-dependent anti-angiogenic factors. Cancer Res. Vol 70(20) . 2010 Oct:8233-8246.
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 TGFß-pathway activity in neuroblastoma. Mol Cell. Vol 40(5) . 2010 Dec:762?773.