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- Thoracic Oncology
- Cancer Physiology
- Cancer Biology and Evolution Program
Education & Training
- University of Pennsylvania & Cancer Research UK Cambridge, PhD - Cell and Molecular Biology
- Beth Israel Deaconess Medical Center & Weill Cornell Medical Collage, Fellow
Cells have energetic and anabolic needs for growth and proliferation. Dr. DeNicola's research is focused on understanding how cells meet these needs and the mechanisms governing the regulation of tumor metabolism in vivo. While cell culture systems are useful for querying the activity of metabolic pathways, many factors in vivo likely play a major role in the regulation of cellular metabolism, including tumor/stroma interactions, contact with the extracellular matrix, local hypoxia and nutrient availability and nutrient intake by the host. The DeNicola laboratory investigates the influence of both genomic alterations and the microenvironment on cellular metabolism in vivo. Mutations in KEAP1 and NRF2, which lead to NRF2 hyperactivation, are commonly found in cancers and lead to metabolic deregulation. Despite the identification of the first KEAP1 mutations in 2006, the precise mechanisms by which NRF2 promotes tumorigenesis are unclear owing to the lack of genetically engineered KEAP1 and NRF2 mutant mouse models that recapitulate the human disease. Dr. DeNicola and others, have identified that NRF2 activation leads to profound deregulation of cellular metabolism, including the promotion of serine biosynthesis, which is critical for the proliferation of KEAP1 and NRF2 mutant cells. However, the activity of these pathways in KEAP1/NRF2 mutant lung tumors in vivo is not established. A major research focus of her lab is investigating how NRF2 promotes tumorigenesis and metabolic deregulation in vivo using genetically engineered mouse model systems. The DeNicola laboratory also focuses on how the microenvironment affects metabolic dependencies. Much of the understanding of tumor metabolism comes from cell culture experiments in which other cell types typically found in tumors, such as fibroblasts and immune cells, are absent. However, these cells have the potential to significantly affect tumor metabolism in vivo by both providing and/or competing for metabolites that the tumor cells require. Her laboratory is examining how the metabolic interaction between epithelial tumor cells with fibroblasts and immune cells affects the metabolism and growth of these compartments.
- Lee SB, Sellers B, DeNicola G. The Regulation of NRF2 by Nutrient-Responsive Signaling and Its Role in Anabolic Cancer Metabolism. Antioxid Redox Signal. 2017 Oct. Pubmedid: 28899208.
- Torrente L, DeNicola GM. Stressing Out PanIN: NRF2 Pushes over the Edge. Cancer Cell. 2017 Dec;32(6):723-725. Pubmedid: 29232549.
- Moon JS, Nakahira K, Chung KP, DeNicola GM, Koo MJ, Pabón MA, Rooney KT, Yoon JH, Ryter SW, Stout-Delgado H, Choi AM. NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat Med. 2016 Sep;22(9):1002-1012. Pubmedid: 27455510. Pmcid: PMC5204248.
- Mullarky E, Lucki NC, Beheshti Zavareh R, Anglin JL, Gomes AP, Nicolay BN, Wong JC, Christen S, Takahashi H, Singh PK, Blenis J, Warren JD, Fendt SM, Asara JM, DeNicola GM, Lyssiotis CA, Lairson LL, Cantley LC. Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proc Natl Acad Sci U S A. 2016 Feb;113(7):1778-1783. Pubmedid: 26831078. Pmcid: PMC4763784.
- Chio II, Jafarnejad SM, Ponz-Sarvise M, Park Y, Rivera K, Palm W, Wilson J, Sangar V, Hao Y, Öhlund D, Wright K, Filippini D, Lee EJ, Da Silva B, Schoepfer C, Wilkinson JE, Buscaglia JM, DeNicola GM, Tiriac H, Hammell M, Crawford HC, Schmidt EE, Thompson CB, Pappin DJ, Sonenberg N, Tuveson DA. NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell. 2016 Aug;166(4):963-976. Pubmedid: 27477511. Pmcid: PMC5234705.
- DeNicola GM, Harris IS. Making sense of reAKTive oxygen species. Cell Death Differ. 2016 Aug;23(8):1269-1270. Pubmedid: 27315299. Pmcid: PMC4947676.
- DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, Tang H, Xie Y, Asara JM, Huffman KE, Wistuba II, Minna JD, DeBerardinis RJ, Cantley LC. Erratum: NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genetics. 2016 Apr;48(4):473. Pubmedid: 27023779.
- DeNicola GM, Karreth FA, Adams DJ, Wong CC. The utility of transposon mutagenesis for cancer studies in the era of genome editing. Genome Biol. 2015 Oct;16:229. Pubmedid: 26481584. Pmcid: PMC4612416.
- DeNicola GM, Cantley LC. Cancer's Fuel Choice: New Flavors for a Picky Eater. Mol Cell. 2015 Nov;60(4):514-523. Pubmedid: 26590711. Pmcid: PMC4676726.
- Moon JS, Hisata S, Park MA, DeNicola GM, Ryter SW, Nakahira K, Choi AM. mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation. Cell Rep. 2015 Jul;12(1):102-115. Pubmedid: 26119735. Pmcid: PMC4858438.
- DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, Tang H, Xie Y, Asara JM, Huffman KE, Wistuba II, Minna JD, DeBerardinis RJ, Cantley LC. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genetics. 2015 Dec;47(12):1475-1481. Pubmedid: 26482881. Pmcid: PMC4721512.
- Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Choo-Wing R, Wulf GM, Bell EL, Shim HS, Lamia KA, Rameh LE, Bellinger G, Sasaki AT, Asara JM, Yuan X, Bullock A, Denicola GM, Song J, Brown V, Signoretti S, Cantley LC. Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors. Cell. 2013 Nov;155(4):844-857. Pubmedid: 24209622. Pmcid: PMC4070383.
- Caldwell ME, DeNicola GM, Martins CP, Jacobetz MA, Maitra A, Hruban RH, Tuveson DA. Cellular features of senescence during the evolution of human and murine ductal pancreatic cancer. Oncogene. 2012 Mar;31(12):1599-1608. Pubmedid: 21860420. Pmcid: PMC3397306.
- Gopinathan A, Denicola GM, Frese KK, Cook N, Karreth FA, Mayerle J, Lerch MM, Reinheckel T, Tuveson DA. Cathepsin B promotes the progression of pancreatic ductal adenocarcinoma in mice. Gut. 2012 Jun;61(6):877-884. Pubmedid: 22157328.
- Karreth FA, Tay Y, Perna D, Ala U, Tan SM, Rust AG, DeNicola G, Webster KA, Weiss D, Perez-Mancera PA, Krauthammer M, Halaban R, Provero P, Adams DJ, Tuveson DA, Pandolfi PP. In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell. 2011 Oct;147(2):382-395. Pubmedid: 22000016. Pmcid: PMC3236086.
- Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, Warren A, Scott H, Madhu B, Sharma N, Bon H, Zecchini V, Smith DM, Denicola GM, Mathews N, Osborne M, Hadfield J, Macarthur S, Adryan B, Lyons SK, Brindle KM, Griffiths J, Gleave ME, Rennie PS, Neal DE, Mills IG. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. Embo J. 2011 May;30(13):2719-2733. Pubmedid: 21602788. Pmcid: PMC3155295.
- Karreth FA, Frese KK, DeNicola GM, Baccarini M, Tuveson DA. C-Raf is required for the initiation of lung cancer by K-Ras(G12D). Cancer Discov. 2011 Jul;1(2):128-136. Pubmedid: 22043453. Pmcid: PMC3203527.
- DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, Tuveson DA. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011 Jul;475(7354):106-109. Pubmedid: 21734707. Pmcid: PMC3404470.
- DeNicola GM, Tuveson DA. RAS in cellular transformation and senescence. Eur J Cancer. 2009 Sep;45 Suppl 1:211-216. Pubmedid: 19775620.
- Karreth FA, DeNicola GM, Winter SP, Tuveson DA. C-Raf inhibits MAPK activation and transformation by B-Raf(V600E). Mol Cell. 2009 Nov;36(3):477-486. Pubmedid: 19917255.
- Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009 Jun;324(5933):1457-1461. Pubmedid: 19460966. Pmcid: PMC2998180.
- Denicola G, Tuveson DA. VAV1: a new target in pancreatic cancer?. Cancer Biol Ther. 2005 May;4(5):509-511. Pubmedid: 15970675.