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:

PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart.

BACKGROUND: Metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. The elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, its role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully illustrated. Here, we aimed to dissect the role of cardiac PKM1 (pyruvate kinase muscle isozyme 1) in glucose metabolic regulation and cardiac response under pressure overload. METHODS: Cardiac-specific deletion of PKM1 was achieved by crossing the floxed PKM1 mouse model with the cardiomyocyte-specific Cre transgenic mouse. PKM1 transgenic mice were generated under the control of tetracycline response elements, and cardiac-specific overexpression of PKM1 was induced by doxycycline administration in adult mice. Pressure overload was triggered by transverse aortic constriction. Primary neonatal rat ventricular myocytes were used to dissect molecular mechanisms. Moreover, metabolomics and nuclear magnetic resonance spectroscopy analyses were conducted to determine cardiac metabolic flux in response to pressure overload. RESULTS: We found that PKM1 expression is reduced in failing human and mouse hearts. It is important to note that cardiomyocyte-specific deletion of PKM1 exacerbates cardiac dysfunction and fibrosis in response to pressure overload. Inducible overexpression of PKM1 in cardiomyocytes protects the heart against transverse aortic constriction-induced cardiomyopathy and heart failure. At the mechanistic level, PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration, and ATP production under pressure overload. Furthermore, deficiency of PKM1 causes a defect in cardiomyocyte growth and a decrease in pyruvate dehydrogenase complex activity at both in vitro and in vivo levels. CONCLUSIONS: These findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.
Authors
Li, Q; Li, C; Elnwasany, A; Sharma, G; An, YA; Zhang, G; Elhelaly, WM; Lin, J; Gong, Y; Chen, G; Wang, M; Zhao, S; Dai, C; Smart, CD; Liu, J; Luo, X; Deng, Y; Tan, L; Lv, S-J; Davidson, SM; Locasale, JW; Lorenzi, PL; Malloy, CR; Gillette, TG; Vander Heiden, MG; Scherer, PE; Szweda, LI; Fu, G; Wang, ZV
MLA Citation
Li, Qinfeng, et al. “PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart.Circulation, vol. 144, no. 9, Aug. 2021, pp. 712–27. Pubmed, doi:10.1161/CIRCULATIONAHA.121.054885.
URI
https://scholars.duke.edu/individual/pub1484426
PMID
34102853
Source
pubmed
Published In
Circulation
Volume
144
Published Date
Start Page
712
End Page
727
DOI
10.1161/CIRCULATIONAHA.121.054885

Metabolomics in cancer research and emerging applications in clinical oncology.

Cancer has myriad effects on metabolism that include both rewiring of intracellular metabolism to enable cancer cells to proliferate inappropriately and adapt to the tumor microenvironment, and changes in normal tissue metabolism. With the recognition that fluorodeoxyglucose-positron emission tomography imaging is an important tool for the management of many cancers, other metabolites in biological samples have been in the spotlight for cancer diagnosis, monitoring, and therapy. Metabolomics is the global analysis of small molecule metabolites that like other -omics technologies can provide critical information about the cancer state that are otherwise not apparent. Here, the authors review how cancer and cancer therapies interact with metabolism at the cellular and systemic levels. An overview of metabolomics is provided with a focus on currently available technologies and how they have been applied in the clinical and translational research setting. The authors also discuss how metabolomics could be further leveraged in the future to improve the management of patients with cancer.
Authors
Schmidt, DR; Patel, R; Kirsch, DG; Lewis, CA; Vander Heiden, MG; Locasale, JW
MLA Citation
Schmidt, Daniel R., et al. “Metabolomics in cancer research and emerging applications in clinical oncology.Ca: A Cancer Journal for Clinicians, vol. 71, no. 4, July 2021, pp. 333–58. Epmc, doi:10.3322/caac.21670.
URI
https://scholars.duke.edu/individual/pub1482071
PMID
33982817
Source
epmc
Published In
Ca: a Cancer Journal for Clinicians
Volume
71
Published Date
Start Page
333
End Page
358
DOI
10.3322/caac.21670

Amino acid variability, tradeoffs and optimality in human diet

While the quality of fat (e.g. saturated/unsaturated) and carbohydrate (e.g. whole grain/simple sugars) intake has been of great interest, less attention has been made to the type of protein and resulting amino acid intake profiles in human diets. Studies at the molecular level however demonstrate that dietary amino acid intake produces substantial effects on health and disease such as cancer by modulating metabolism. How these effects may manifest in human food consumption and dietary patterns is unknown. We developed a series of algorithms to map, characterize and model the landscape of amino acid content in human food, dietary patterns, and individual consumption including relations to health status, covering over 2,000 foods, ten dietary patterns, and over 30,000 dietary records. We found that the type of amino acids contained in foods and human consumption is highly dynamic with variability far exceeding that of fat and carbohydrate. Some amino acids positively associate with diseases such as obesity while others contained in the same food negatively link to disease. Using linear programming and machine learning, we show that these health trade-offs among can be accounted to satisfy biochemical constraints in food and human eating patterns to construct a Pareto front in dietary practice, a means of achieving optimality in the face of tradeoffs that are commonly considered in economic and evolutionary theories. Thus this study may enable the design of human protein quality intake guidelines based on a quantitative framework.
Authors
Dai, Z; Locasale, J
MLA Citation
Dai, Ziwei, and Jason Locasale. Amino acid variability, tradeoffs and optimality in human diet. June 2021. Epmc, doi:10.1101/2021.06.16.448627.
URI
https://scholars.duke.edu/individual/pub1485729
Source
epmc
Published Date
DOI
10.1101/2021.06.16.448627

Integrated Metabolic and Gene Expression Profiling Reveals New Therapeutic Modalities for Rapidly Proliferating Breast Cancers

<jats:title>Abstract</jats:title> <jats:p>Metabolic dysregulation, although a prominent feature in breast cancer, remains undercharacterized in patient tumors. By performing untargeted metabolomics analyses on triple-negative breast cancer (TNBC) and Estrogen Receptor (ER) positive patient breast tumors, as well as TNBC patient-derived xenografts (PDXs), we identified two major metabolic groups independent of breast cancer histological subtypes: a “Nucleotide/Carbohydrate-Enriched” group and a “Lipid/Fatty Acid-Enriched” group. Cell lines grown in vivo more faithfully recapitulate the metabolic profiles of patient tumors. Integrated metabolic and gene expression analyses reveal genes that strongly correlate with metabolic dysregulation and predict patient prognosis. As a proof-of-principle, targeting Nucleotide/Carbohydrate-Enriched TNBC cell line or PDX xenografts with a pyrimidine biosynthesis inhibitor, and/or a glutaminase inhibitor, led to therapeutic efficacy. In addition, the pyrimidine biosynthesis inhibitor presents better therapeutic outcomes than chemotherapy agents in multiple murine TNBC models. Our study provides a new stratification of breast tumor samples based on integrated metabolic and gene expression profiling, which guides the selection of newly effective therapeutic strategies targeting rapidly proliferating breast cancer subsets. In addition, we develop a public, interactive data visualization portal (http://brcametab.org) based on the data generated from this study.</jats:p>
Authors
Liao, C; Glodowski, CR; Fan, C; Liu, J; Mott, KR; Kaushik, A; Vu, H; Locasale, J; McBrayer, SK; DeBerardinis, R; Perou, C; Zhang, Q
MLA Citation
Liao, Chengheng, et al. Integrated Metabolic and Gene Expression Profiling Reveals New Therapeutic Modalities for Rapidly Proliferating Breast Cancers. Research Square Platform LLC. Crossref, doi:10.21203/rs.3.rs-117384/v2.
URI
https://scholars.duke.edu/individual/pub1492957
Source
crossref
DOI
10.21203/rs.3.rs-117384/v2

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

<jats:p>Activating macrophage NLRP3 inflammasome can promote excessive inflammation, leading to severe cell and tissue damage and organ dysfunction. Here, we showed that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuated macrophage NLRP3 inflammasome activation. Broad rewiring of intracellular metabolism and enhanced autophagic flux occurred in inflammasome-activated macrophages, but neither was necessary for the PDHK-regulated reduction of NLRP3 inflammasome activity. PDHK inhibition protected against inflammation-induced mitochondrial fragmentation and cristae remodeling and improved mitochondrial function by repurposing mitochondria from ROS production to ATP generation. Inhibition of PDHK increased the expression of the mitochondrial fusion protein optic atrophy-1 (OPA1). Suppression of OPA1 partially reversed the effect of PDHK inhibition on NLRP3 inflammasome activation. In conclusion, our study suggests that inhibition of PDHK dampens macrophage NLRP3 inflammasome activation during acute inflammation by ameliorating mitochondrial damage in a mechanism separate from its canonical role as a metabolic regulator.</jats:p>
Authors
Meyers, AK; Wang, Z; Han, W; Zhao, Q; Zabalawi, M; Liu, J; Manne, RK; Lin, H-K; Furdui, CM; Locasale, JW; McCall, CM; Zhu, X
MLA Citation
Meyers, Allison K., et al. Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation. Cold Spring Harbor Laboratory. Crossref, doi:10.1101/2021.10.02.462869.
URI
https://scholars.duke.edu/individual/pub1498262
Source
crossref
DOI
10.1101/2021.10.02.462869