Jason Locasale

Overview:

Our research interests are in three interconnected areas:  1) Quantitative and computational biology of metabolism. 2) The role of diet and pharmacological therapeutics in shaping metabolic pathways in health and cancer.  3) The interaction of metabolism and epigenetics.  Each of these synergistic areas utilizes the metabolomics technologies we develop along with our expertise in computational and molecular biology.

Positions:

Associate Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of Duke Molecular Physiology Institute

Duke Molecular Physiology Institute
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.A. 2003

Rutgers University New Brunswick

Ph.D. 2008

Massachusetts Institute of Technology

Publications:

Cutting Edge: Elevated Glycolytic Metabolism Limits the Formation of Memory CD8+ T Cells in Early Life.

Neonates often develop poor immunity against intracellular pathogens. Because CD8+ T cells are essential for eliminating infectious agents, it is crucial to understand why they behave differently in early life. Previous studies in mice have demonstrated that neonatal CD8+ T cells fail to form memory because of an intrinsic propensity to differentiate into short-lived effectors. However, the underlying mechanisms remain undefined. We now show that neonatal CD8+ T cells exhibit higher glycolytic activity than adult CD8+ T cells postinfection, which may be due to age-related differences in Lin28b expression. Importantly, when glycolysis is pharmacologically inhibited, the impaired formation of neonatal memory CD8+ T cells can be restored. Collectively, these data suggest that neonatal CD8+ T cells are inherently biased toward undergoing glycolytic metabolism postinfection, which compromises their ability to develop into memory CD8+ T cells in early life.
Authors
Tabilas, C; Wang, J; Liu, X; Locasale, JW; Smith, NL; Rudd, BD
MLA Citation
Tabilas, Cybelle, et al. “Cutting Edge: Elevated Glycolytic Metabolism Limits the Formation of Memory CD8+ T Cells in Early Life..” J Immunol, vol. 203, no. 10, Nov. 2019, pp. 2571–76. Pubmed, doi:10.4049/jimmunol.1900426.
URI
https://scholars.duke.edu/individual/pub1415002
PMID
31597706
Source
pubmed
Published In
J Immunol
Volume
203
Published Date
Start Page
2571
End Page
2576
DOI
10.4049/jimmunol.1900426

Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer.

Protein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.
Authors
Zurlo, G; Liu, X; Takada, M; Fan, C; Simon, JM; Ptacek, TS; Rodriguez, J; von Kriegsheim, A; Liu, J; Locasale, JW; Robinson, A; Zhang, J; Holler, JM; Kim, B; Zikánová, M; Bierau, J; Xie, L; Chen, X; Li, M; Perou, CM; Zhang, Q
MLA Citation
Zurlo, Giada, et al. “Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer..” Nat Commun, vol. 10, no. 1, Nov. 2019. Pubmed, doi:10.1038/s41467-019-13168-4.
URI
https://scholars.duke.edu/individual/pub1421409
PMID
31729379
Source
pubmed
Published In
Nature Communications
Volume
10
Published Date
Start Page
5177
DOI
10.1038/s41467-019-13168-4

Quantitative analysis of the physiological contributions of glucose to the TCA cycle

ABSTRACT The carbon source for catabolism in vivo is a fundamental question in metabolic physiology. Limited by data and rigorous mathematical analysis, many controversial statements exist on the metabolic sources for carbon usage in the tricarboxylic acid (TCA) cycle under physiological settings. Using isotope-labeling data in vivo across several experimental conditions, we construct multiple models of central carbon metabolism and develop methods based on metabolic flux analysis (MFA) to solve for the preferences of glucose, lactate, and other nutrients used in the TCA cycle across many tissues. We show that in nearly all circumstances, glucose contributes more than lactate as a nutrient source for the TCA cycle. This conclusion is verified in different animal strains, different administrations of 13C glucose, and is extended to multiple tissue types after considering multiple nutrient sources. Thus, this quantitative analysis of organismal metabolism defines the relative contributions of nutrient fluxes in physiology, provides a resource for analysis of in vivo isotope tracing data, and concludes that glucose is the major nutrient used for catabolism in mammals.
Authors
Liu, S; Dai, Z; Cooper, D; Kirsch, D; Locasale, J
MLA Citation
Liu, Shiyu, et al. Quantitative analysis of the physiological contributions of glucose to the TCA cycle. Nov. 2019. Epmc, doi:10.1101/840538.
URI
https://scholars.duke.edu/individual/pub1421408
Source
epmc
Published Date
DOI
10.1101/840538

Author Correction: Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Authors
Langston, PK; Nambu, A; Jung, J; Shibata, M; Aksoylar, HI; Lei, J; Xu, P; Doan, MT; Jiang, H; MacArthur, MR; Gao, X; Kong, Y; Chouchani, ET; Locasale, JW; Snyder, NW; Horng, T
MLA Citation
Langston, P. Kent, et al. “Author Correction: Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses..” Nat Immunol, vol. 20, no. 11, Nov. 2019. Pubmed, doi:10.1038/s41590-019-0517-8.
URI
https://scholars.duke.edu/individual/pub1411837
PMID
31551573
Source
pubmed
Published In
Nat Immunol
Volume
20
Published Date
Start Page
1555
DOI
10.1038/s41590-019-0517-8

Methionine metabolism in health and cancer: a nexus of diet and precision medicine.

Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer pathogenesis. Intriguingly, the levels of methionine obtained from the diet can have a large effect on cellular methionine metabolism. This establishes a link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet. Recently, a number of studies have begun to investigate the molecular and cellular mechanisms that underlie the interaction between nutrition, methionine metabolism and effects on health and cancer.
Authors
Sanderson, SM; Gao, X; Dai, Z; Locasale, JW
MLA Citation
Sanderson, Sydney M., et al. “Methionine metabolism in health and cancer: a nexus of diet and precision medicine..” Nat Rev Cancer, vol. 19, no. 11, Nov. 2019, pp. 625–37. Pubmed, doi:10.1038/s41568-019-0187-8.
URI
https://scholars.duke.edu/individual/pub1411838
PMID
31515518
Source
pubmed
Published In
Nat Rev Cancer
Volume
19
Published Date
Start Page
625
End Page
637
DOI
10.1038/s41568-019-0187-8