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:

Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses.

Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we find that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosts glucose oxidation to fuel the production of acetyl coenzyme A, acetylation of histones and induction of genes encoding inflammatory mediators. While acute exposure to LPS drives macrophage activation, prolonged exposure to LPS triggers tolerance to LPS, where macrophages induce immunosuppression to limit the detrimental effects of sustained inflammation. The shift in the inflammatory response is modulated by GPD2, which coordinates a shutdown of oxidative metabolism; this limits the availability of acetyl coenzyme A for histone acetylation at genes encoding inflammatory mediators and thus contributes to the suppression of inflammatory responses. Therefore, GPD2 and the glycerol phosphate shuttle integrate the extent of microbial stimulation with glucose oxidation to balance the beneficial and detrimental effects of the inflammatory response.
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; Synder, NW; Horng, T
MLA Citation
Langston, P. Kent, et al. “Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses..” Nat Immunol, vol. 20, no. 9, Sept. 2019, pp. 1186–95. Pubmed, doi:10.1038/s41590-019-0453-7.
URI
https://scholars.duke.edu/individual/pub1402229
PMID
31384058
Source
pubmed
Published In
Nat Immunol
Volume
20
Published Date
Start Page
1186
End Page
1195
DOI
10.1038/s41590-019-0453-7

Metabolic landscape of the tumor microenvironment at single cell resolution.

The tumor milieu consists of numerous cell types each existing in a different environment. However, a characterization of metabolic heterogeneity at single-cell resolution is not established. Here, we develop a computational pipeline to study metabolic programs in single cells. In two representative human cancers, melanoma and head and neck, we apply this algorithm to define the intratumor metabolic landscape. We report an overall discordance between analyses of single cells and those of bulk tumors with higher metabolic activity in malignant cells than previously appreciated. Variation in mitochondrial programs is found to be the major contributor to metabolic heterogeneity. Surprisingly, the expression of both glycolytic and mitochondrial programs strongly correlates with hypoxia in all cell types. Immune and stromal cells could also be distinguished by their metabolic features. Taken together this analysis establishes a computational framework for characterizing metabolism using single cell expression data and defines principles of the tumor microenvironment.
Authors
Xiao, Z; Dai, Z; Locasale, JW
MLA Citation
Xiao, Zhengtao, et al. “Metabolic landscape of the tumor microenvironment at single cell resolution..” Nat Commun, vol. 10, no. 1, Aug. 2019. Pubmed, doi:10.1038/s41467-019-11738-0.
URI
https://scholars.duke.edu/individual/pub1406338
PMID
31434891
Source
pubmed
Published In
Nature Communications
Volume
10
Published Date
Start Page
3763
DOI
10.1038/s41467-019-11738-0

Dietary methionine influences therapy in mouse cancer models and alters human metabolism.

Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component1, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine-the reduction of which has anti-ageing and anti-obesogenic properties-influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (KrasG12D/+;Trp53-/-) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism-and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.
Authors
Gao, X; Sanderson, SM; Dai, Z; Reid, MA; Cooper, DE; Lu, M; Richie, JP; Ciccarella, A; Calcagnotto, A; Mikhael, PG; Mentch, SJ; Liu, J; Ables, G; Kirsch, DG; Hsu, DS; Nichenametla, SN; Locasale, JW
MLA Citation
Gao, Xia, et al. “Dietary methionine influences therapy in mouse cancer models and alters human metabolism..” Nature, vol. 572, no. 7769, Aug. 2019, pp. 397–401. Pubmed, doi:10.1038/s41586-019-1437-3.
URI
https://scholars.duke.edu/individual/pub1402288
PMID
31367041
Source
pubmed
Published In
Nature
Volume
572
Published Date
Start Page
397
End Page
401
DOI
10.1038/s41586-019-1437-3

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis.

Successful metastasis requires the co-evolution of stromal and cancer cells. We used stable isotope labeling of amino acids in cell culture coupled with quantitative, label-free phosphoproteomics to study the bidirectional signaling in ovarian cancer cells and human-derived, cancer-associated fibroblasts (CAFs) after co-culture. In cancer cells, the interaction with CAFs supported glycogenolysis under normoxic conditions and induced phosphorylation and activation of phosphoglucomutase 1, an enzyme involved in glycogen metabolism. Glycogen was funneled into glycolysis, leading to increased proliferation, invasion, and metastasis of cancer cells co-cultured with human CAFs. Glycogen mobilization in cancer cells was dependent on p38α MAPK activation in CAFs. In vivo, deletion of p38α in CAFs and glycogen phosphorylase inhibition in cancer cells reduced metastasis, suggesting that glycogen is an energy source used by cancer cells to facilitate metastatic tumor growth.
Authors
Curtis, M; Kenny, HA; Ashcroft, B; Mukherjee, A; Johnson, A; Zhang, Y; Helou, Y; Batlle, R; Liu, X; Gutierrez, N; Gao, X; Yamada, SD; Lastra, R; Montag, A; Ahsan, N; Locasale, JW; Salomon, AR; Nebreda, AR; Lengyel, E
MLA Citation
Curtis, Marion, et al. “Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis..” Cell Metab, vol. 29, no. 1, Jan. 2019, pp. 141-155.e9. Pubmed, doi:10.1016/j.cmet.2018.08.007.
URI
https://scholars.duke.edu/individual/pub1346868
PMID
30174305
Source
pubmed
Published In
Cell Metab
Volume
29
Published Date
Start Page
141
End Page
155.e9
DOI
10.1016/j.cmet.2018.08.007

Thermodynamic constraints on the regulation of metabolic fluxes

Abstract Nutrition and metabolism are fundamental to cellular function in physiological and pathological contexts. Metabolic activity (i.e. rates, flow, or most commonly referred to as flux) is constrained by thermodynamics and regulated by the activity of enzymes. The general principles that relate biological and physical variables to metabolic control are incompletely understood. Using metabolic control analysis in several representative topological structures of metabolic pathways as models, we derive exact results and conduct computer simulations that define relationships between thermodynamics, enzyme activity, and flux control. We confirm that metabolic pathways that are very far from equilibrium are controlled by the activity of upstream enzymes. However, in general, metabolic pathways have a more adaptable pattern of regulation, controlled minimally by thermodynamics and not necessarily by the specific enzyme that generates the given reaction. These findings show how the control of metabolic pathways, which are rarely very far from equilibrium, is largely set by the overall flux through a pathway rather than by the enzyme which generates the flux or by thermodynamics.
Authors
Dai, Z; Locasale, J
MLA Citation
Dai, Ziwei, and Jason Locasale. Thermodynamic constraints on the regulation of metabolic fluxes. June 2018. Epmc, doi:10.1101/341271.
URI
https://scholars.duke.edu/individual/pub1330958
Source
epmc
Published Date
DOI
10.1101/341271