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:

Cooperative virus propagation underlies COVID-19 transmission dynamics

The global pandemic due to the emergence of a novel coronavirus (COVID-19) is a threat to the future health of humanity. There remains an urgent need to understand its transmission characteristics and design effective interventions to mitigate its spread. In this study, we define a non-linear (known in biochemistry models as allosteric or cooperative) relationship between viral shedding, viral dose and COVID-19 infection propagation. We develop a mathematical model of the dynamics of COVID-19 to link quantitative features of viral shedding, human exposure and transmission in nine countries impacted by the ongoing COVID-19 pandemic. The model was then used to evaluate the efficacy of interventions against virus transmission. We found that cooperativity was important to capture country-specific transmission dynamics and leads to resistance to mitigating transmission in mild or moderate interventions. The behaviors of the model emphasize that strict interventions greatly limiting both virus shedding and human exposure are indispensable to achieving effective containment of COVID-19.
Authors
Dai, Z; Locasale, J
MLA Citation
Dai, Ziwei, and Jason Locasale. Cooperative virus propagation underlies COVID-19 transmission dynamics. May 2020. Epmc, doi:10.1101/2020.05.05.20092361.
URI
https://scholars.duke.edu/individual/pub1439767
Source
epmc
Published Date
DOI
10.1101/2020.05.05.20092361

A reactive metabolite as an immune suppressant.

Authors
Ramesh, V; Locasale, JW
MLA Citation
Ramesh, Vijyendra, and Jason W. Locasale. “A reactive metabolite as an immune suppressant.Nature Immunology, vol. 21, no. 5, May 2020, pp. 497–98. Epmc, doi:10.1038/s41590-020-0664-y.
URI
https://scholars.duke.edu/individual/pub1437934
PMID
32327751
Source
epmc
Published In
Nature Immunology
Volume
21
Published Date
Start Page
497
End Page
498
DOI
10.1038/s41590-020-0664-y

NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in patients with cancer. The metabolic properties of these cells are likely to be distinct from those of rapidly growing tumours. Here we show that Her2 downregulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and patients with breast cancer with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, whereas suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.
Authors
Fox, DB; Garcia, NMG; McKinney, BJ; Lupo, R; Noteware, LC; Newcomb, R; Liu, J; Locasale, JW; Hirschey, MD; Alvarez, JV
MLA Citation
Fox, D. B., et al. “NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.” Nature Metabolism, vol. 2, no. 4, Apr. 2020, pp. 318–34. Scopus, doi:10.1038/s42255-020-0191-z.
URI
https://scholars.duke.edu/individual/pub1437935
Source
scopus
Published In
Nature Metabolism
Volume
2
Published Date
Start Page
318
End Page
334
DOI
10.1038/s42255-020-0191-z

Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer.

Local adaptation directs populations towards environment-specific fitness maxima through acquisition of positively selected traits. However, rapid environmental changes can identify hidden fitness trade-offs that turn adaptation into maladaptation, resulting in evolutionary traps. Cancer, a disease that is prone to drug resistance, is in principle susceptible to such traps. We therefore performed pooled CRISPR-Cas9 knockout screens in acute myeloid leukemia (AML) cells treated with various chemotherapies to map the drug-dependent genetic basis of fitness trade-offs, a concept known as antagonistic pleiotropy (AP). We identified a PRC2-NSD2/3-mediated MYC regulatory axis as a drug-induced AP pathway whose ability to confer resistance to bromodomain inhibition and sensitivity to BCL-2 inhibition templates an evolutionary trap. Across diverse AML cell-line and patient-derived xenograft models, we find that acquisition of resistance to bromodomain inhibition through this pathway exposes coincident hypersensitivity to BCL-2 inhibition. Thus, drug-induced AP can be leveraged to design evolutionary traps that selectively target drug resistance in cancer.
Authors
Lin, KH; Rutter, JC; Xie, A; Pardieu, B; Winn, ET; Bello, RD; Forget, A; Itzykson, R; Ahn, Y-R; Dai, Z; Sobhan, RT; Anderson, GR; Singleton, KR; Decker, AE; Winter, PS; Locasale, JW; Crawford, L; Puissant, A; Wood, KC
MLA Citation
Lin, Kevin H., et al. “Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer.Nature Genetics, vol. 52, no. 4, Apr. 2020, pp. 408–17. Epmc, doi:10.1038/s41588-020-0590-9.
URI
https://scholars.duke.edu/individual/pub1435937
PMID
32203462
Source
epmc
Published In
Nature Genetics
Volume
52
Published Date
Start Page
408
End Page
417
DOI
10.1038/s41588-020-0590-9

The Na+/K+ ATPase Regulates Glycolysis and Defines Immunometabolism in Tumors

ABSTRACT Cancer therapies targeting metabolism have been limited due to a lack of understanding of the controlling properties of vulnerable pathways. The Na + /K + ATPase is responsible for a large portion of cellular energy demands but how these demands influence metabolism and create metabolic liabilities are not known. Using metabolomic approaches, we first show that digoxin, a cardiac glycoside widely used in humans, acts through disruption to central carbon metabolism via on target inhibition of the Na + /K + ATPase that was fully recovered by expression of an allele resistant to digoxin. We further show in vivo that administration of digoxin inhibits glycolysis in both malignant and healthy cells, particularly within clinically relevant cardiac tissue, while exhibiting tumor-specific cytotoxic activity in an allografted soft tissue sarcoma. Single-cell expression analysis of over 31,000 cells within the sarcoma shows that acute Na + /K + ATPase inhibition shifts the immune composition of the tumor microenvironment, leading to selective transcriptional reprogramming of metabolic processes in specific immune cells thus acting both through tumor cell autonomous and non-autonomous (e.g. macrophage) cells. These results provide evidence that altering energy demands can be used to regulate glycolysis with specific cell-type specific consequences in a multicellular environment.
Authors
Sanderson, S; Xiao, Z; Wisdom, A; Bose, S; Liberti, M; Reid, M; Hocke, E; Gregory, S; Kirsch, D; Locasale, J
MLA Citation
Sanderson, Sydney, et al. The Na+/K+ ATPase Regulates Glycolysis and Defines Immunometabolism in Tumors. Apr. 2020. Epmc, doi:10.1101/2020.03.31.018739.
URI
https://scholars.duke.edu/individual/pub1436687
Source
epmc
Published Date
DOI
10.1101/2020.03.31.018739