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Thales Y. Papagiannakopoulos

Thales Y. Papagiannakopoulos, PhD

Assistant Professor, Department of Pathology

Keywords
CRISPR/Cas9, Lung Cancer, mouse models, cancer, oxidative stress, metabolism, circadian rhythms, cancer, NRF2, KEAP1, GEMM
Summary
Development of novel in vivo genome engineering approaches for cancer research

Cancer develops from mutations and copy number alterations in oncogenes and tumor suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Our lab is pioneering the use of GEMMs of lung cancer in combination with in vivo CRISPR/Cas9 genome engineering approaches to address the immediate need to systematically interrogate the complex catalog of mutations obtained from cancer genome sequencing studies.

In the era of personalized medicine, CRISPR/Cas9-based approaches provide invaluable tools to tackle the complexity of cancers. The extensive information recorded from an individual patient tumor can be functionally validated using a platform that makes use of both in vitro and in vivo CRIPSR/Cas9-based approaches. Once important functional variants are identified, genetic and drug screens can be performed to identify genotype-specific vulnerabilities that may pave the road to new personalized genotype-based therapies, which is the ultimate goal of precision medicine.

Elucidating the role of physiologic and metabolic factors in lung tumorigenesis Metabolic reprogramming, oxidative stress and lung cancer

Kras-driven non-small cell lung cancer (NSCLC) remains one of the most aggressive and lethal solid tumors. ~20% of Kras-driven NSCLC acquire mutually exclusive activating mutations in the anti-oxidant transcription factor NRF2 or inactivating mutations in its negative regulator KEAP1. The anti-oxidant transcription factor NRF2 acts as the primary line of cellular defense against reactive oxygen species (ROS) by rewiring metabolism to maintain oxidative homeostasis.

Using a combination of a Kras-driven genetically engineered mouse model and somatic CRISPR/Cas9 genome-engineering approaches we have demonstrated the functional importance of NRF2/KEAP1 pathway in lung tumorigenesis. Using both metabolomic and focused genetic screening methods we are systematically indentifying novel mechanisms underlying the role of Nrf2/Keap1 pathway in lung cancer. We find unique metabolic dependancies in Nrf2/Keap1 mutant lung cancer cells which we validate by both genetic and biochmeical approaches. These dependancies highlight metabolic vulnerabilities in cells with increased anti-oxidant production due to alteration in the Nrf2/Keap1 pathway, which can we are exploiting as novel metabolism-based therapeutic strategies for lung cancer.

Circadian rhythm disruption promotes lung cancer

Circadian rhythm disruption by shift-work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor suppressive role for circadian rhythm homeostasis. Circadian rhythms are 24-hour oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism.Despite extensive characterization of genetic events that contribute to cancer, the impact of environmental/physiologic factors on tumorigenesis remains poorly understood. A major consequence of a modern lifestyle is the disruption of circadian rhythms. A plethora of epidemiological studies have revealed that the risk for many types of cancer, including lung, is significantly higher among shift-workers. In 2010, the World Health Organization and the International Agency for Research on Cancer, published an assessment on carcinogenicity of shift-work which concluded: “shift-work that involves circadian disruption is probably carcinogenic to humans”. This raises many concerns, since in the US alone, it is estimated that 20% of the US work force is subjected to shifting work schedule.

Using GEMMs of lung cancer, we are characterizing the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression.

Phone

646-501-0042

Academic office

550 First Avenue, Smilow Building

5th floor, Room 505

New York, NY 10016

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Assistant Professor, Department of Pathology

PhD from University of California at Santa Barbara

Fellowship, Massachusetts Institute of Technology, Tyler Jacks

Sayin, Volkan I; Papagiannakopoulos, Thales

Cancer letters. 2017 02 28; 387:10-17

Sanchez-Rivera, Francisco J; Papagiannakopoulos, Thales; Romero, Rodrigo; Tammela, Tuomas; Bauer, Matthew R; Bhutkar, Arjun; Joshi, Nikhil S; Subbaraj, Lakshmipriya; Bronson, Roderick T; Xue, Wen; Jacks, Tyler

Nature. 2014 Dec 18; 516(7531):428-31

Li, Fei; Huang, Qingyuan; Luster, Troy A; Hu, Hai; Zhang, Hua; Ng, Wai-Lung; Khodadadi-Jamayran, Alireza; Wang, Wei; Chen, Ting; Deng, Jiehui; Ranieri, Michela; Fang, Zhaoyuan; Pyon, Val; Dowling, Catriona M; Bagdatlioglu, Ece; Almonte, Christina; Labbe, Kristen; Silver, Heather; Rabin, Alexandra R; Jani, Kandarp; Tsirigos, Aristotelis; Papagiannakopoulos, Thales; Hammerman, Peter S; Velcheti, Vamsidhar; Freeman, Gordon J; Qi, Jun; Miller, George; Wong, Kwok-Kin

Cancer discovery. 2019 Nov 19;

Sayin, Volkan I; LeBoeuf, Sarah E; Papagiannakopoulos, Thales

Trends in cancer. 2019 Aug; 5(8):457-459

Lignitto, Luca; LeBoeuf, Sarah E; Homer, Harrison; Jiang, Shaowen; Askenazi, Manor; Karakousi, Triantafyllia R; Pass, Harvey I; Bhutkar, Arjun J; Tsirigos, Aristotelis; Ueberheide, Beatrix; Sayin, Volkan I; Papagiannakopoulos, Thales; Pagano, Michele

Cell. 2019 Jul 11; 178(2):316-329.e18

McLoughlin, Michael R; Orlicky, David J; Prigge, Justin R; Krishna, Pushya; Talago, Emily A; Cavigli, Ian R; Eriksson, Sofi; Miller, Colin G; Kundert, Jean A; Sayin, Volkan I; Sabol, Rachel A; Heinemann, Joshua; Brandenberger, Luke O; Iverson, Sonya V; Bothner, Brian; Papagiannakopoulos, Thales; Shearn, Colin T; Arnér, Elias S J; Schmidt, Edward E

Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2019 Jun 04; 116(23):11408-11417

Garcia-Bermudez, Javier; Baudrier, Lou; La, Konnor; Zhu, Xiphias Ge; Fidelin, Justine; Sviderskiy, Vladislav O; Papagiannakopoulos, Thales; Molina, Henrik; Snuderl, Matija; Lewis, Caroline A; Possemato, Richard L; Birsoy, Kıvanç

Nature cell biology. 2018 Oct; 20(10):1228

Snuderl, Matija; Kannan, Kasthuri; Pfaff, Elke; Wang, Shiyang; Stafford, James M; Serrano, Jonathan; Heguy, Adriana; Ray, Karina; Faustin, Arline; Aminova, Olga; Dolgalev, Igor; Stapleton, Stacie L; Zagzag, David; Chiriboga, Luis; Gardner, Sharon L; Wisoff, Jeffrey H; Golfinos, John G; Capper, David; Hovestadt, Volker; Rosenblum, Marc K; Placantonakis, Dimitris G; LeBoeuf, Sarah E; Papagiannakopoulos, Thales Y; Chavez, Lukas; Ahsan, Sama; Eberhart, Charles G; Pfister, Stefan M; Jones, David T W; Karajannis, Matthias A

Nature communications. 2018 07 20; 9(1):2868