T32 Targeting Tumor Cell Biology Program – Trainees

Postdoc Trainees

Anna Groner, PhD

Anna Groner

Anna earned her Ph.D. in 2011 from the Swiss Federal Institute of Technology. She joined the lab of Professor Myles Brown at Dana-Farber Cancer Institute where she works on understanding the mechanisms behind castration-resistant prostate cancer. Using a combination of genetic and genomic approaches, she has shown that TRIM24 protein is upregulated by prostate cancer driver mutations, and that this upregulation augments androgen receptor signaling. Because TRIM24 is also essential for the proliferation of castration-resistant prostate cancer cells, this provides a rationale for the therapeutic targeting of TRIM24 in this stage of the disease.

Publications

  • Theurillat JP, Udeshi ND, Errington WJ, Svinkina T, Baca SC, Pop M, Wild PJ, Blattner M, Groner AC, Rubin MA, Moch H, Prive GG, Carr SA, Garraway LA. Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer. Science. 2014 Oct 3:346(6205):85-9.

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  • Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, Wu X, Stack EC, Loda M, Liu T, Xu H, Cato L, Thornton JE, Gregory RI, Morrissey C, Vessella RL, Montironi R, Magi-Galluzzi C, Kantoff PW, Balk SP, Liu XS, Brown M. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012 Dec 14;338(6113):1465-9. PMCID: PMC3625962.

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Abhishek Chakraborty, PhD

Abhishek joined Professor Kaelin’s lab at Dana-Farber Cancer Institute after earning his Ph.D. in 2009 from the State University of New York, Stony Brook. He studies the role of the pVHL tumor suppressor in clear cell renal carcinoma, the most common form of kidney cancer in adults. Current therapies have poor results and many side effects. Abhishek is using shRNA screens to identify novel targets in VHL-null cells, particularly of chromatin modifiers tumor cells upregulate in response to loss of VHL.

Publications

  • Olenchock BA, Moslehi J, Baik AH, Davidson SM, Williams J, Gibson WJ, Chakraborty AA, Pierce KA, Miller CM, Hanse EA, Kelekar A, Sullivan LB, Wagers AJ, Clish CB, Vander Heiden MG, Kaelin WG Jr. (2016), EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection, Cell, 164: 884-95.

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  • Zheng X, Zhai B, Koivunen P, Shin SJ, Lu G, Liu J, Geisen C, Chakraborty AA, Moslehi JJ, Smalley DM, Wei X, Chen X, Chen Z, Beres JM, Zhang J, Tsao JL, Brenner MC, Zhang Y, Fan C, DePinho RA, Paik J, Gygi SP, Kaelin WG Jr, Zhang Q. Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes Dev. 2014 Jul 1;28(13):1429-44. PMCID: PMC4083087.

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Xueliang (Gary) Gao, PhD

Xueliang (Gary) Gao began his training in the lab of Professor Roberts at Dana-Farber Cancer Institute after earning his Ph.D. from Georgia State University in 2010. He studies the role of PTEN, a phosphatase lost in the PI3K pathway in castration-resistant prostate cancers. Resistant prostate tumors express the activated p110β isoform of PI3K. Using genetically engineered mouse models, he has found that p110β plays a critical role in the initiation and progression of PTEN null resistant tumors.

Publications

  • Utermark T, Schmit F, Lee SH, Gao X, Schaffhausen BS, Roberts TM. The phosphatidylinositol 3-kinase (PI3K) isoform dependence of tumor formation is determined by the genetic mode of PI3K pathway activation rather than by tissue type. J Virol. 2014 Sep;88(18):10673-9. PMCID: PMC4178865.

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  • Korpal M, Korn JM*, Gao X*, Rakiec DP, Ruddy DA, Doshi S, Yuan J, Kovats SG, Kim S, Cooke VG, Monahan JE, Stegmeier F, Roberts TM, Sellers WR, Zhou W, Zhu P. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov. 2013 Sep;3(9):1030-43.

    * Denotes authors making equal contributions.

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  • Jia S*, Gao X*, Lee SH, Maira SM, Wu X, Stack EC, Signoretti S, Loda M, Zhao JJ, Roberts TM. Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. Cancer Discov. 2013 Jan;3(1):44-51. PMCID: PMC3546223.

    * Denotes authors making equal contributions.

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Amie Holmes, PhD

Amie joined the lab of Professor Alan D’Andrea at Dana-Farber Cancer Institute after earning her Ph.D, from the University of Maine in 2011. She studies the role of the cohesin complex in DNA damage repair in acute myelogenous leukemia. Using CRISPR knockdown technology, she has shown loss of the cohesion component SMC3 confers sensitivity to PARP inhibitors and mitomycin C, suggesting that loss of SMC3 leads to a DNA repair defect.

Justin Hwang, PhD

Justin is a postdoctoral fellow in the laboratory of Professor Hahn at Dana-Farber Cancer Institute. He earned his Ph.D. in 2014 from Tufts University. Justin is studying the mechanism by which androgen-dependent prostate cancers become resistant to androgen therapy. Using a genetic screening approach, he has identified several candidate genes that may drive the growth of androgen-independent prostate cancers, and is the process of validating their function in vitro and in vivo.

Publications

  • Hwang JH, Pores Fernando AT, Faure N, Andrabi S, Adelmant G, Hahn WC, Marto JA, Schaffhausen BS, Roberts TM. Correction for Hwang et al., Polyomavirus small T antigen interacts with yes-associated protein to regulate cell survival and differentiation. J Virol. 2015 Jul;89(13):6971. PMCID: PMC4468481.

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  • White EA, Kramer RE, Hwang JH, Pores Fernando AT, Naetar N, Hahn WC, Roberts TM, Schaffhausen BS, Livingston DM, Howley PM. Papillomavirus E7 oncoproteins share functions with polyomavirus small T antigens. J Virol. 2015 Mar;89(5):2857-65. PMCID: PMC4325735.

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  • Hwang JH, Pores Fernando AT, Faure N, Andrabi S, Adelmant G, Hahn WC, Marto JA, Schaffhausen BS, Roberts TM. Polyomavirus small T antigen interacts with yes-associated protein to regulate cell survival and differentiation. J Virol. 2014 Oct;88(20):12055-64. PMCID: PMC4178709

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Rebecca Meyer

Rebecca joined the lab of Professor John Flanagan at Harvard Medical School after completing her PhD at Emory University in 2013. Her research project is focused on identifying and characterizing novel mechanisms of transcriptional regulation through cell surface receptors.  Using biochemical and gene analysis techniques she is examining the transcriptional role of receptor tyrosine kinases in cell proliferation, migration, and general disease progression in cancer cell samples.

Gloria Sheynkman, PhD

Gloria earned her PhD in 2014 from the University of Wisconsin. She is a postdoctoral fellow in the lab of Professor Marc Vidal at Dana-Farber Cancer Institute and is investigating the functional significance of alternative splicing at proteome scale.  Alternative splicing is frequently misregulated during carcinogenesis, contributing to rewiring of cellular pathways that drive proliferation, apoptosis, and other hallmarks of cancer.  Much knowledge of splicing stems from studies on differential expression of alternatively spliced mRNAs rather than on protein function. Consequently, there is a large gap in our knowledge of the function and significance of alternatively spliced proteins in normal and cancer biology, especially on a proteome-wide scale. The Center for Cancer Systems Biology at Dana-Farber Cancer Institute recently mapped the first protein isoform interactome, demonstrating that alternative isoforms are involved in diverse organizational, functional, and cross-tissue network dynamics.  Remarkably, two isoforms from the same gene can be functionally just as different from each other as distinct proteins encoded by two separate genes.  Expanding upon the original isoform interactome study, Gloria has begun work towards empirically building and analyzing the first cancer-specific isoform interaction network. This project will be the first global picture of the consequences and functional effects of aberrant splicing in cancer.

Publications

  • Yang X, Coulombe-Huntington J, Kang S, Sheynkman GM, Hao T, Richardson A, Sun S, Yang F, Shen YA, Murray RR, Spirohn K, Begg BE, Duran-Frigola M, MacWilliams A, Pevzner SJ, Zhong Q, Trigg SA, Tam S, Ghamsari L, Sahni N, Yi S, Rodriguez MD, Balcha D, Tan G, Costanzo M, Andrews B, Boone C, Zhou XJ, Salehi-Ashtiani K, Charloteaux B, Chen AA, Calderwood MA, Aloy P, Roth FP, Hill DE, Iakoucheva LM, Xia Y, Vidal M. Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell. 2016 Feb 11;164(4):805-17.

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Nicole Vincent Jordan , PhD

Nicole joined the lab of Professor Daniel Haber at Harvard Medical School in 2013 after completing her PhD at the University of North Carolina. Advanced cancers are thought to be comprised of heterogeneous cell populations that evolve as a result of therapeutic interventions, leading to the acquisition of drug resistance. A recent report detailed the ability to culture tumor cells isolated from the blood of women with advanced breast cancer (circulating tumor cells or CTCs), establishing the technology to isolate and interrogate previously inaccessible multidrug-resistant, patient-derived cancer cells and study their composition using whole proteome analysis. Nicole found that proliferating CTCs from multiple patients with advanced estrogen receptor-positive/HER2-negative breast cancer can be neatly divided into two different subpopulations. One subpopulation has acquired HER2 expression, displays activation of multiple RTK signaling pathways and is highly proliferative, in vitro and in vivo; the other population lacks HER2 expression but has elevated Notch1 levels, and while it is less proliferative, in vitro and in vivo, it is highly resistant to cytotoxic agents (but relatively sensitive to Notch1 inhibitors). Together, these results point to distinct phenotypes displayed by heterogeneous subpopulations of patient-derived circulating tumor cells, contributing to the progression of breast cancer and the acquisition of drug resistance.

Publications

  • Ting DT, Wittner BS, Ligorio M, Vincent Jordan N, Shah AM, Miyamoto DT, Aceto N, Bersani F, Brannigan BW, Xega K, Ciciliano JC, Zhu H, MacKenzie OC, Trautwein J, Arora KS, Shahid M, Ellis HL, Qu N, Bardeesy N, Rivera MN, Deshpande V, Ferrone CR, Kapur R, Ramaswamy S, Shioda T, Toner M, Maheswaran S, Haber DA. Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. Cell Rep. 2014 Sep 25;8(6):1905-18. PMCID: PMC4230325.

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Predoc Trainees

Sanchez Jarrett

Sanchez is a graduate student at Harvard Medical School in the laboratory of Professor Stephen Blacklow. Sanchez graduated with a BA from Brooklyn College in 2014. His thesis research is focused on Notch signaling in cancer, in particular T cell lymphocytic leukemia. He is studying how the Notch regulated ankyrin repeat protein (NRARP) acts as a negative regulator of Notch signaling using proteomic and structural analysis.

Liv Johannessen

Liv is a graduate student at Harvard Medical School in the laboratory of Professor Nathanael Gray at Dana-Farber Cancer Institute. She graduated with a BS from Maryland College in 2012. Liv is studying how cyclin-dependent kinases (CDKs) regulate signaling pathways, in particular how CDK8 regulates IL10 in immune regulation.

Publications

  • Tan L, Akahane K, McNally R, Reyskens KM, Ficarro SB, Liu S, Herter-Sprie GS, Koyama S, Pattison MJ, Labella K, Johannessen L, Akbay EA, Wong KK, Frank DA, Marto JA, Look TA, Arthur JS, Eck MJ, Gray NS. Development of Selective Covalent Janus Kinase 3 Inhibitors. J Med Chem. 2015 Aug 27;58(16):6589-606. PMCID: PMC4777322.

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Ryan Kuzmickas

Ryan joined Dr. Karen Cichowski’s group in 2009 as a graduate student after earning his BA from George Washington University. His research is focused on developing novel therapies for advanced prostate cancer. In spite of the effort and expense devoted to developing therapies for advanced prostate cancer, relatively little progress has been made since the introduction of androgen ablation therapy over 70 years ago. EZH2 is one of the most highly-expressed proteins in advanced prostate cancer, which has previously demonstrated its function as a key driver of lethal metastatic prostate cancer. EZH2 is the enzymatic component of Polycomb Repressive Complex 2 (PRC2), which transcriptionally silences genes through methylation of lysine 27 on histone h3. This project examines combining EZH2 inhibition with inhibition of other epigenetic modifiers in order to achieve a therapeutic effect in advanced prostate cancer. Histones can also be acetylated, an epigenetic mark correlated with gene activation. By combining EZH2 inhibition with the inhibition of Histone Deacetylases (HDACs) Ryan has been able to achieve a combined anti-tumor effect both in vitro and in vivo. Current research focuses on elucidating the mechanism of this effect, which involves a synergistic potentiation of transcriptional activation.