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:

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

Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.

Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.
Authors
Di Conza, G; Tsai, C-H; Gallart-Ayala, H; Yu, Y-R; Franco, F; Zaffalon, L; Xie, X; Li, X; Xiao, Z; Raines, LN; Falquet, M; Jalil, A; Locasale, JW; Percipalle, P; Masson, D; Huang, SC-C; Martinon, F; Ivanisevic, J; Ho, P-C
MLA Citation
Di Conza, Giusy, et al. “Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.Nat Immunol, vol. 22, no. 11, Nov. 2021, pp. 1403–15. Pubmed, doi:10.1038/s41590-021-01047-4.
URI
https://scholars.duke.edu/individual/pub1499519
PMID
34686867
Source
pubmed
Published In
Nat Immunol
Volume
22
Published Date
Start Page
1403
End Page
1415
DOI
10.1038/s41590-021-01047-4

TGF-β/HDAC7 axis suppresses TCA cycle metabolism in renal cancer.

Mounting evidence points to alterations in mitochondrial metabolism in renal cell carcinoma (RCC). However, the mechanisms that regulate the TCA cycle in RCC remain uncharacterized. Here, we demonstrate that loss of TCA cycle enzyme expression is retained in RCC metastatic tissues. Moreover, proteomic analysis demonstrates that reduced TCA cycle enzyme expression is far more pronounced in RCC relative to other tumor types. Loss of TCA cycle enzyme expression is correlated with reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) which is also lost in RCC tissues. PGC-1α re-expression in RCC cells restores the expression of TCA cycle enzymes in vitro and in vivo and leads to enhanced glucose carbon incorporation into TCA cycle intermediates. Mechanistically, TGF-β signaling, in concert with histone deacetylase 7 (HDAC7), suppresses TCA cycle enzyme expression. Our studies show that pharmacologic inhibition of TGF-β restores the expression of TCA cycle enzymes and suppresses tumor growth in an orthotopic model of RCC. Taken together, this investigation reveals a novel role for the TGF-β/HDAC7 axis in global suppression of TCA cycle enzymes in RCC and provides new insight into the molecular basis of altered mitochondrial metabolism in this malignancy.
Authors
Nam, H; Kundu, A; Karki, S; Brinkley, GJ; Chandrashekar, DS; Kirkman, RL; Liu, J; Liberti, MV; Locasale, JW; Mitchell, T; Varambally, S; Sudarshan, S
MLA Citation
Nam, Hyeyoung, et al. “TGF-β/HDAC7 axis suppresses TCA cycle metabolism in renal cancer.Jci Insight, Oct. 2021. Pubmed, doi:10.1172/jci.insight.148438.
URI
https://scholars.duke.edu/individual/pub1498261
PMID
34609963
Source
pubmed
Published In
Jci Insight
Published Date
DOI
10.1172/jci.insight.148438