RESEARCH

Overview

Cancer is a multistep process that involves the complex interplay of both genetic and environmental factors that contribute to tumor progression. Our laboratory uses genetically engineered mouse models, which recapitulate the genetics, heterogeneity, histological progression and tissue microenvironment of human tumors. Using these mouse models, we can dissect the interactions of cancer cells and the tumor microenvironment and determine how systemic changes in metabolism, physiology and diet can impact tumor progression.

A major focus of our laboratory is to study the major genetic subtypes of KRAS-driven lung cancer. Using CRISPR/Cas9-based somatic genome engineering and unbiased genetic screens, we have developed a platform to rapidly characterize the function of clinically relevant lung cancer mutations, elucidate their mechanism of action and identify novel targeted therapies against these aggressive genetic subtypes of lung cancer.  

Feeding the beast: Understanding cancer metabolism

We are investigating how mutations in metabolic genes in the NRF2/KEAP1 and LKB1 pathways, which are frequent in lung cancers, can influence tumor initiation and progression by rewiring cellular metabolism. We use a combination of genetic and biochemical approaches to identify metabolic liabilities that can be exploited using novel targeted therapies.

Our laboratory has demonstrated the role of NRF2/KEAP1 mutations in promoting antioxidant metabolism during tumor progression. We have demonstrated the therapeutic potential of targeting multiple metabolic pathways in pre-clinical models with NRF2/KEAP1 mutations. Our group continues to investigate the mechanisms underlying novel metabolic dependencies in NRF2/KEAP1 mutant and other genetic subtypes of lung cancer.

Articles

Ding H*, Chen Z*, Wu K*, Huang SM, Wu WL, LeBoeuf SE, Pillai RG, Rabinowitz JD, Papagiannakopoulos T. Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition. Science Advances. 2021. Read the article

LeBoeuf SE*, Wu WL*, Karakousi TR, Karadal B, Jackson SR, Davidson SM, Wong KK, Koralov SB, Sayin VI, Papagiannakopoulos T. Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids. Cell Metabolism. 2019. Read the article

Lignitto L; LeBoeuf SE; Homer H; Jiang S; Askenazi M; Karakousi TR; Pass HI; Bhutkar AJ; Tsirigos A; Ueberheide B; Papagiannakopoulos T.#, Pagano M.# Nrf2 activation promotes lung cancer metastasis by blocking degradation of Bach1. Cell. 2019. Read the article

Romero R*, Sayin VI*; Davidson SM; Bauer MR; Singh SX; LeBoeuf SE; Karakousi TR; Ellis DC; Bhutkar A; Sánchez-Rivera FJ; Subbaraj L; Martinez B; Bronson RT; Prigge JR; Schmidt EE; Thomas CJ; Goparaju C; Davies A; Dolgalev I; Heguy A; Allaj V; Poirier JT; Moreira AL; Rudin CM; Pass HI; Vander Heiden MG; Jacks T#; Papagiannakopoulos T#. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med. 2017. Read the article

Sayin VI*; LeBoeuf SE*; Singh SX; Davidson SM; Biancur D; Guzelhan BS; Alvarez SW; Wu WL; Karakousi TR; Zavitsanou AM; Ubriaco J; Muir A; Karagiannis D; Morris PJ; Thomas CJ; Possemato R, Vander Heiden MG; Papagiannakopoulos T. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife. 2017. Read the article

Review Articles

Pillai R, Hayashi M, Zavitsanou AM, Papagiannakopoulos T. NRF2: KEAPing Tumors Protected. Cancer Discovery. 2022. Read the article

Wu WL, Papagiannakopoulos T. The Pleiotropic Role of the KEAP1/NRF2 Pathway in Cancer. Annual Reviews of Cancer Biology. 2020. Read the article

Lung cancer immune surveillance

Immune-based therapies for lung cancer have yielded limited responses. Despite encouraging results, the overall response rate to immune modulators in the context of KRAS-driven lung cancer has remained less than 30%. Emerging clinical data suggests that mutations that frequently co-occur with KRAS may impact response to immunotherapy. Immune cells have distinct metabolic requirements that enable their proper activation and differentiation in order to mount an anti-tumor response. However, it remains unknown how mutations impact tumor cell autonomous metabolic reprogramming and alter the metabolic milieu in the tumor microenvironment to suppress anti-tumor immune responses.

Leveraging our unique expertise in cancer biology, genetically-defined mouse models, metabolism and collaborative efforts with the greater NYU immunology community, we are investigating how driver mutations shape the immune microenvironment and impact the infiltration and function of innate and adaptive immune cells.

Articles

Zavitsanou AM, Hao Y, Wu WL…. Papagiannakopoulos T#, Koralov SB#. KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. bioRxiv doi: 10.1101/2021.09.24.461709v1. Read the article

Circadian Rhythms and Cancer

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.

Using mouse models, we are characterizing the effects of circadian rhythm disruption on lung cancer progression. We have demonstrated that both physiologic perturbation by jet-lag and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. Our studies provide direct evidence that circadian disruption can play a causal role in cancer progression by altering both cell-autonomous and distant tissue circadian homeostasis. We are currently investigating whether cell autonomous circadian clock homeostasis is altered during tumorigenesis leading to disruption of the circadian transcriptome, which may contribute to tumor progression and heterogeneity.

Articles

Papagiannakopoulos, T., Bauer, M., Davidson, S., Heimann, M. , Subbaraj, L., Bhutkar, A., Bartlebaugh, J., Vander Heiden, M., Jacks, T. Circadian Rhythm Disruption Promotes Lung Tumorigenesis. Cell Metabolism. (2016). Read the article

Masri S, Papagiannakopeoulos T, Kinouchi K, Liu Y, Cervantes M, Baldi P, Jacks T, Sassone-Corsi P. Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis. Cell. 2016. Read the article

Genome engineering approaches

Our laboratory uses genetically engineered mouse models of lung cancer in combination with CRISPR/Cas9-based somatic genome engineering tools. Using these CRISPR/Cas9-based GEMMs, we have developed a platform to rapidly characterize the function of clinically relevant lung cancer mutations, elucidate their mechanism of action and identify novel targeted therapies against complex genetic subtypes of lung cancer.

Article

Sánchez-Rivera, F. J. and Papagiannakopoulos, T. et al, Nature, 2014. Read the article