Faculty

Andrei Thomas-Tikhonenko, Ph.D.

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

Contact information
4056 Colket Translational Research Bldg
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

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

Research Interests

Since its inception in 1997, the Thomas-Tikhonenko laboratory was 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 in adults and children alike. Yet their exact roles in promoting neoplastic growth in genetically complex human cancers remained only partially understood.

The major breakthrough in the field was the discovery of MYC-regulated microRNAs, in particular the miR-17~92 cluster, which is transcriptionally induced by both c- and N-Myc. 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 TGFβ 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. Subsequent studies also demonstrated that miR-17~92 participates in a cross-talk between TGFβ and WNT pathways, forming oncogenic feed-forward loops (Lanauze et al, Mol Cancer Res 2021; Sehgal et al, Mol Cancer Res 2021).

To determine the contribution of Myc to malignant growth in hematopoietic tissues, we 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; Chang et al, 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 involved in therapeutic apoptosis and chemoresistance (Harrington et al, Leukemia 2019; Harrington et al, Trends Cancer 2021) and last but not least - B-cell receptor signaling. The role of BCR and its co-receptor CD19 in promoting lymphomagenesis was the focus of the two key papers published in early ‘10s (Chung et al, J Clin Invest 2012; Psathas et al, Blood 2013).

As CD19 became recognized as the major target for immunotherapy in general and chimeric antigen receptor-armed autologous T cells (CARTs) in particular, we dedicated major effort towards elucidating the mechanism of epitope loss in post-CART19 relapses of acute lymphoblastic leukemia. This work was aided by our participation in the multi-institutional Stand Up to Cancer-St. Baldrick's Pediatric Cancer Dream Team (2013-2022; 2021 AACR Team Science Award). Using whole exome and RNA sequencing, we identified two alternatively spliced CD19 mRNA species: one lacking exons 5-6 (Δex5-6), which encode the transmembrane domain, and another lacking exon 2 (Δex2). We further showed that skipping of exon 2 compromised surface localization of CD19 and yielded truncated CD19 protein variants, which fail to trigger killing by CART-19 (Sotillo et al, Cancer Discovery 2015; Bagashev et al, Mol Cell Biol 2018; Black et al, Nucl Acids Res 2018). Subsequent work identified additional aberrant splicing events (e.g., CD19 intron 2 retention) as major drivers of resistant to CD19-directed immunotherapy (Asnani et al, Leukemia 2020; Cortés-López et al, Nat Commun 2022) as well as similar splicing-based mechanisms of epitope loss affecting other targets (Zheng et al, Blood Cancer Discov 2022; Cai et al, Nat Commun 2022).

Since 2018, the Thomas-Tikhonenko lab has been an integral part of the Pediatric Immunotherapy Discovery and Development Network (PI-DDN) funded through Beau Biden Cancer Moonshot Initiative. Our most recent work informed the central hypothesis that non-canonical exon usage plays a dual role in leukemia and other pediatric cancers. On the one hand, it provides cancers with intrinsic mechanisms of epitope loss, which can render targeted immunotherapy ineffective. On the other hand, alternative splicing could be a source of cancer-specific epitopes and as such could aid immunotherapy. By simultaneously exploring the effects of alternative splicing on antigen loss and neo-epitope gain, we aspire to lay ground for the development of new immunotherapeutics that would target pediatric cancers with the specificity current modalities do not possess.

Rotation Projects
1. To investigate the effects of aberrant splicing of cell surface antigens on cancer immunotherapy (CAR T cells, antibody-drug conjugates, etc)
2. To elucidate post-transcriptional mechanisms of cancer chemoresistance (aberrant splicing, protein degradation, etc.)
3. To identify determinants of aberrant splicing in cancer, with focus on genetic variants and RNA-binding proteins

Lab personnel
Priyanka Sehgal, PhD, Research Associate
Manuel Torres Diz, PhD, Research Associate
Zhiwei Ang, PhD, Research Associate
Charles Drummer IV, PhD, T32 Postdoctoral Fellow
Scarlett Yang, Immunology (IGG) Graduate Student
Carolin Schmidt, Research Technician II
Katharina Hayer, Bioinformatics Scientist III
Rawan Shraim, Bioinformatics Scientist I
Jacob Stanger, Penn Undergraduate Student
Hayden Siesel, Penn Undergraduate Student
Paty King, Penn Undergraduate Student
Kayla Ji, Penn Undergraduate Student
Kathryn Wurges, MHA/MHE, Project Manager

Affiliated personnel
Mathieu Quesnel-Vallières, PhD (Postdoctoral Fellow in the Barash/Lynch labs @Penn)
David Wang (GCB Graduate Student in the Barash lab @Penn)

Recent alumni
Sisi Zheng, MD, Pediatric Hem-Onc Fellow
Ammar Naqvi, PhD, Postdoctoral Fellow
Mukta Asnani, PhD, Postdoctoral Fellow
Colleen Harrington, CAMB Graduate Student
Claudia Lanauze, CAMB Graduate Student

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Description of Other Expertise

In 2008, I moved my lab across campus to The Children's Hospital of Philadelphia, where it became an integral part of the Center for Childhood Cancer Research. This integration allowed me to foster new collaborations with key physician-scientists and pursue multiple translational projects focused on (but not limited to) pediatric malignancies.

Selected Publications

M.Cortés-López, L.Schulz, M.Enculescu, C.Paret, B.Spiekermann, M.Quesnel-Vallières, M.Torres-Diz, S.Unic, A.Busch, A.Orekhova, M Kuban, M.Mesitov, M.Mulorz, R.Shraim, F.Kielisch, J.Faber, Y.Barash, A.Thomas-Tikhonenko, K.Zarnack, S.Legewie, J.König: High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance. Nat Commun in press 2022.

T.Cai, A.Gouble, K.L.Black, A.S.Naqvi, D.Taylor, M.Zhao, Q.Yuan, M.Sugita, R.Galetto, S.Filipe, A.Cavazos, L.Han, Q.Zhang, V.Kuruvilla, H.Ma, C.G.Liu, X.Liu, S.Konoplev, J.Gu, G.Tang, X.Su, G.Al-Atrash, S.Ciurea, S.S.Neelapu, A.A.Lane, H.Kantarjian, M.L.Guzman, N.Pemmaraju, J.Smith, A.Thomas-Tikhonenko, and M.Konopleva: Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells. Nat Commun 13: 2228, Apr 2022.

S.Zheng, E.Gillespie, Ammar S. Naqvi, K.E.Hayer, Z.Ang, M.Torres-Diz, M.Quesnel-Vallières, D.A.Hottman, A.Bagashev, J.Chukinas, C.Schmidt, M.Asnani, R.Shraim, D.M.Taylor, S.R.Rheingold, M.M.O’Brien, N.Singh, K.W.Lynch, M.Ruella, Y.Barash, S.K.Tasian, and A.Thomas-Tikhonenko: Modulation of CD22 protein expression in childhood leukemia by pervasive splicing aberrations: implications for CD22-directed immunotherapy. Blood Cancer Discov 3(2): 103–115, Mar 2022.

P.Sehgal, C.Lanauze, X.Wang, K.E.Hayer, M.Torres-Diz, N.A.Leu, Y.Sela, B.Z.Stanger, C.J. Lengner, and A.Thomas-Tikhonenko: MYC hyperactivates WNT signaling in APC/CTNNB1-mutated colorectal cancer cells through miR-92a-dependent repression of DKK3. Mol Cancer Res 19(12): 2003-2014, Dec 2021.

C.T.Harrington, E.Sotillo, C.V.Dang, and A.Thomas-Tikhonenko: Tilting MYC toward cancer cell death Trends Cancer 7(11): 982-994, Nov 2021.

P.S.Choi and A.Thomas-Tikhonenko: RNA-binding proteins of COSMIC significance in cancer. J Clin Invest 131(18): e151627, Sep 2021.

L.Schulz, M.Torres-Diz, M.Cortés-López, K.E.Hayer, M.Asnani, S.K.Tasian, Y.Barash, E.Sotillo, K.Zarnack, J.König, and A.Thomas-Tikhonenko: Direct long-read RNA sequencing identifies a subset of questionable exitrons likely arising from reverse transcription artifacts. Genome Biol 22(1): 190, June 2021.

C.B.Lanauze, P.Sehgal, K.Hayer, M.Torres-Diz, J.A.Pippin, S.F.A.Grant, and A.Thomas-Tikhonenko: Colorectal cancer-associated Smad4 R361 hotspot mutations boost Wnt/β-catenin signaling through enhanced Smad4-LEF1 binding. Mol Cancer Res 19(5): 823-833, May 2021.

M.Asnani, K.E.Hayer, A.S.Naqvi, S.Zheng, S.Y.Yang, D.Oldridge, F.Ibrahim, M.Maragkakis, M.R.Gazzara, K.L.Black, A.Bagashev, D.Taylor, Z.Mourelatos, S.A.Grupp, D.Barrett, J.M.Maris, E.Sotillo, Y.Barash, and A.Thomas-Tikhonenko: Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia 34(4): 1202–1207, Apr 2020.

C.T.Harrington, E.Sotillo, A.Robert, K.E.Hayer, A.M.Bogusz, J.Psathas, D.Yu, D.Taylor, C.V.Dang, P.Klein, M.D.Hogarty, B.Geoerger, W.S.El-Deiry, J.Wiels, and A.Thomas-Tikhonenko : Transient stabilization, rather than inhibition of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma. Leukemia 33(10): 2429–2441, Oct 2019.

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Last updated: 08/08/2022
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