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.
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, neuroblastoma, B-lymphoma, leukemia, immunotherapy
Description of Research
My laboratory is broadly interested in the mechanisms of neoplastic transformation by the Myc family oncoproteins (including c- and N-Myc). The corresponding genes are altered via chromosomal translocation in B-cell lymphomas and are amplified or otherwise deregulated in many solid malignancies. Yet their exact roles in promoting neoplastic growth in genetically complex human cancers remain only partially understood. The major breakthrough in the field was the discovery of MYC-regulated microRNAs, in particular the miR-17~92 cluster.
Early on, we were able to demonstrate that in solid tumors, such as pediatric neuroblastoma 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 (Chayka et al, J Natl Cancer Inst 2009; Dews et al, Cancer Res 2010; Mestdagh et al, Mol Cell 2010, Sundaram et al, Cancer Res 2011, Fox et al, RNA 2013; Dews et al, J Natl Cancer Inst 2014). This brings about robust tumor neovascularization and enhanced neoplastic growth. In fact, our ?06 discovery that miR-17~92 augments tumor angiogenesis (Dews et al, Nature Genet 2006) was the first example of the involvement of microRNAs in non-cell-autonomous tumor phenotypes and vascular biology.
To determine the contribution of c-Myc to malignant growth in hematopoietic tissues, we have developed several new mouse models for B-cell lymphoma based on infection of p53-deficient bone marrow progenitors by Myc-encoding retroviruses (Yu et al, Blood 2007; Cozma et al, J Clin Invest 2007; Amaravadi et al, J Clin Invest 2007). Unexpectedly, we discovered that the salient feature of Myc-induced lymphomagenesis was not only overexpression of the oncogenic miR-17-92 but also repression of several tumor suppressive microRNAs, such as miR-15/16 and miR-34 (Chang et al, Nature Genet 2008 & Proc Natl Acad Sci 2009, Sotillo et al, Oncogene 2011). These microRNAs affect c-Myc expression levels and contribute to deregulation of multiple Myc target genes, therapeutic apoptosis and last but not least - B-cell receptor signaling. In the last two years we focused our attention on that last aspect of lymphoma biology. The role of BCR/CD19 signaling in lymphomagenesis is the focus of our two most recent papers: Chung et al, J Clin Invest 2012, and Psathas et al, Blood 2013. We are currently investigating deregulation of CD19 as a key mechanism of treatment failure in various blood cancers.
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.
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
Ariella Sasson, PhD, Bioinformatician (part-time)
Colleen Harrington, CAMB Graduate Student
Marcela Robaina, Visiting Scientist (INCA, Rio de Janeiro, Brazil)
Claudia Lanauze, CAMB Graduate Student
Glendon Wu, IGG Graduate Student (Spring '15 rotation)
Kathryn Wurges, MHA/MHE, Resource Coordinator II
- Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2013– present)
- Associate Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2008 – 2013)
- Professor of Pediatrics at University of Pennsylvania School of Medicine (2015– present)
- PhD, Oncology/Virology, Russian Academy of Medical Sciences (1988)
- BSc, Biochemistry/Virology, Moscow State University (1984)
- J.N.Psathas and A.Thomas-Tikhonenko. MYC and the art of microRNA maintenance. Cold Spring Harb Perspect Med. Vol in press. 2013.
- 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.
- 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.