Nathan Ward, PhD

The Ward Lab focuses on characterizing the influence of systemic metabolism and the tumor microenvironment on mitochondrial redox biology in primary and metastatic lung tumors. We achieve this through the implementation of mass-spec based -omics platforms, redox biosensors, and super-resolution microscopy.

Associations

• Metabolism and Physiology
• Cancer Biology & Evolution Program

My research program is centered on the intersection between metabolic compartmentalization and mitochondrial biology. We are interested in evaluating how the spatial distribution of cofactors, metabolites, and proteins dictate mitochondria metabolic function in support of lung tumor growth and resilience in response to nutrient scarcity and therapy. Within the context of lung cancer, we are currently focused on elucidating the following: i) how the Fe-S cluster synthesis pathway is coordinated to meet the varied cellular demands associated with tumorigenesis, ii) does substrate channeling of reducing equivalents exist across cellular compartments, and iii) do metabolic enzymes exhibit non-canonical functions (e.g. scaffolding) associated with their differential sub-organellar distribution.

• Messina MS, Torrente L, Pezacki AT, Humpel HI, Li EL, Miller SG, Verdejo-Torres O, Padilla-Benavides T, Brady DC, Killilea DW, Killilea AN, Ralle M, Ward NP, Ohata J, DeNicola GM, Chang CJ. A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer. Proc Natl Acad Sci U S A. 2025 Jan.122(3). Pubmedid: 39813247. Pmcid: PMC11761388.
• Hecht F, Zocchi M, Tuttle ET, Ward NP, Smith B, Kang YP, Cazarin J, Soares ZG, Ozgurses ME, Zhao H, Sheehan C, Alimohammadi F, Munger LD, Trivedi D, Asantewaa G, Blick-Nitko SK, Zoeller JJ, Chen Y, Vasiliou V, Turner BM, Muir A, Coloff JL, Munger J, DeNicola GM, Harris IS. Catabolism of extracellular glutathione supplies amino acids to support tumor growth. bioRxiv. 2024 Oct. Pubmedid: 39416022. Pmcid: PMC11482906.
• Ward NP, Yoon SJ, Flynn T, Sherwood AM, Olley MA, Madej J, DeNicola GM. Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC. Nat Commun. 2024 May.15(1):4244. Pubmedid: 38762605. Pmcid: PMC11102494.
• Pezacki AT, Gonciarz RL, Okamura T, Matier CD, Torrente L, Cheng K, Miller SG, Ralle M, Ward NP, DeNicola GM, Renslo AR, Chang CJ. A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools. Proc Natl Acad Sci U S A. 2024 Jul.121(28). Pubmedid: 38968123. Pmcid: PMC11252945.
• Asantewaa G, Tuttle ET, Ward NP, Kang YP, Kim Y, Kavanagh ME, Girnius N, Chen Y, Rodriguez K, Hecht F, Zocchi M, Smorodintsev-Schiller L, Scales TQ, Taylor K, Alimohammadi F, Duncan RP, Sechrist ZR, Agostini-Vulaj D, Schafer XL, Chang H, Smith ZR, O'Connor TN, Whelan S, Selfors LM, Crowdis J, Gray GK, Bronson RT, Brenner D, Rufini A, Dirksen RT, Hezel AF, Huber AR, Munger J, Cravatt BF, Vasiliou V, Cole CL, DeNicola GM, Harris IS. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression. Nat Commun. 2024 Jul.15(1):6152. Pubmedid: 39034312. Pmcid: PMC11271484.
• Greenwood HE, Barber AR, Edwards RS, Tyrrell WE, George ME, Dos Santos SN, Baark F, Tanc M, Khalil E, Falzone A, Ward NP, DeBlasi JM, Torrente L, Soni PN, Pearce DR, Firth G, Smith LM, Vilhelmsson Timmermand O, Huebner A, Swanton C, Hynds RE, DeNicola GM, Witney TH. Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography. Nat Commun. 2024 Dec.15(1):10484. Pubmedid: 39690148. Pmcid: PMC11652680.
• Ward NP. Cys-regulation: oxidized CHK1 controls cross-compartment circuit of chemoresistance. Trends Cancer. 2023 Sep.9(9):700-702. Pubmedid: 37532649.
• Ilter D, Drapela S, Schild T, Ward NP, Adhikari E, Low V, Asara J, Oskarsson T, Lau EK, DeNicola GM, McReynolds MR, Gomes AP. NADK-mediated de novo NADP(H) synthesis is a metabolic adaptation essential for breast cancer metastasis. Redox Biol. 2023 May.61:102627. Pubmedid: 36841051. Pmcid: PMC9982641.
• Dutta T, Kapoor N, Mathew M, Chakraborty SS, Ward NP, Prieto-Farigua N, Falzone A, DeLany JP, Smith SR, Coen PM, DeNicola GM, Gardell SJ. Source of nicotinamide governs its metabolic fate in cultured cells, mice, and humans. Cell Rep. 2023 Mar.42(3):112218. Pubmedid: 36897780.
• Asantewaa G, Tuttle ET, Ward NP, Kang YP, Kim Y, Kavanagh ME, Girnius N, Chen Y, Duncan R, Rodriguez K, Hecht F, Zocchi M, Smorodintsev-Schiller L, Scales TQ, Taylor K, Alimohammadi F, Sechrist ZR, Agostini-Vulaj D, Schafer XL, Chang H, Smith Z, O'Connor TN, Whelan S, Selfors LM, Crowdis J, Gray GK, Bronson RT, Brenner D, Rufini A, Dirksen RT, Hezel AF, Huber AR, Munger J, Cravatt BF, Vasiliou V, Cole CL, DeNicola GM, Harris IS. Glutathione supports lipid abundance in vivo. bioRxiv. 2023 Feb. Pubmedid: 36798186. Pmcid: PMC9934595.
• Greenwood HE, Edwards RS, Tyrrell WE, Barber AR, Baark F, Tanc M, Khalil E, Falzone A, Ward NP, DeBlasi JM, Torrente L, Pearce DR, Firth G, Smith LM, Timmermand OV, Huebner A, George ME, Swanton C, Hynds RE, DeNicola GM, Witney TH. Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography. bioRxiv. 2023 Dec. Pubmedid: 38168428. Pmcid: PMC10760199.
• Ravichandran M, Hu J, Cai C, Ward NP, Venida A, Foakes C, Kuljanin M, Yang A, Hennessey CJ, Yang Y, Desousa BR, Rademaker G, Staes AAL, Cakir Z, Jain IH, Aguirre AJ, Mancias JD, Shen Y, DeNicola GM, Perera RM. Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer. Cancer Discov. 2022 Sep.12(9):2198-2219. Pubmedid: 35771494. Pmcid: PMC9444964.
• Van Oss SB, Parikh SB, Coelho NC, Wacholder A, Belashov I, Zdancewicz S, Michaca M, Xu J, Kang YP, Ward NP, Yoon SJ, McCourt KM, McKee J, Ideker T, VanDemark AP, DeNicola GM, Carvunis AR. On the illusion of auxotrophy: met15Δ yeast cells can grow on inorganic sulfur, thanks to the previously uncharacterized homocysteine synthase Yll058w. J Biol Chem. 2022 Dec.298(12):102697. Pubmedid: 36379252. Pmcid: PMC9763685.
• Jiang C, Ward NP, Prieto-Farigua N, Kang YP, Thalakola A, Teng M, DeNicola GM. A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer. Redox Biol. 2022 Aug.54:102358. Pubmedid: 35667246. Pmcid: PMC9168196.
• Ward NP, DeNicola GM. Long-sought mediator of vitamin K recycling discovered. Nature. 2022 Aug.608(7924):673-674. Pubmedid: 35922487.
• Jiang C, Ward NP, Prieto-Farigua N, Kang YP, Thalakola A, Teng M, DeNicola GM. Corrigendum to "A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer" [Redox Biol. 54 (2022) 102358]. Redox Biol. 2022 Aug.54:102393. Pubmedid: 35794066. Pmcid: PMC9287741.
• Ward NP, DeNicola GM. GSH hoards all the cysteine-what a slimy thing to do. Nat Metab. 2021 Mar.3(3):297-298. Pubmedid: 33664498.
• Ward NP, Kang YP, Falzone A, Boyle TA, DeNicola GM. Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function. J Exp Med. 2020 Jun.217(6). Pubmedid: 32196080. Pmcid: PMC7971138.
• Ward NP, DeNicola GM. The Golgi: Keeping It Unapologetically Basic. Cancer Discov. 2020 Jun.10(6):768-770. Pubmedid: 32482665.
• Koutnik AP, Poff AM, Ward NP, DeBlasi JM, Soliven MA, Romero MA, Roberson PA, Fox CD, Roberts MD, D'Agostino DP. Ketone Bodies Attenuate Wasting in Models of Atrophy. J Cachexia Sarcopenia Muscle. 2020 Aug.11(4):973-996. Pubmedid: 32239651. Pmcid: PMC7432582.
• Ward NP, DeNicola GM. Sulfur metabolism and its contribution to malignancy. Int Rev Cell Mol Biol. 2019 Aug.347:39-103. Pubmedid: 31451216.
• Kang YP, Ward NP, DeNicola GM. Recent advances in cancer metabolism: a technological perspective. Exp Mol Med. 2018 Apr.50(4):1-16. Pubmedid: 29657324. Pmcid: PMC5938018.