James Alvarez

Positions:

Assistant Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1999

Pennsylvania State University

Ph.D. 2005

Harvard Medical School

Grants:

Par-4 Regulation and Function in Breast Cancer Dormancy and Recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Pathways regulating dormant cell survival and recurrence

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
End Date

Publications:

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

Optical Imaging of Glucose Uptake and Mitochondrial Membrane Potential to Characterize Her2 Breast Tumor Metabolic Phenotypes.

With the large number of women diagnosed and treated for breast cancer each year, the importance of studying recurrence has become evident due to most deaths from breast cancer resulting from tumor recurrence following therapy. To mitigate this, cellular and molecular pathways used by residual disease prior to recurrence must be studied. An altered metabolism has long been considered a hallmark of cancer, and several recent studies have gone further to report metabolic dysfunction and alterations as key to understanding the underlying behavior of dormant and recurrent cancer cells. Our group has used two probes, 2-[N-(7-nitrobenz-2-oxa-1, 3-diaxol-4-yl) amino]-2-deoxyglucose (2-NBDG) and tetramethyl rhodamine ethyl ester (TMRE), to image glucose uptake and mitochondrial membrane potential, respectively, to report changes in metabolism between primary tumors, regression, residual disease, and after regrowth in genetically engineered mouse (GEM)-derived mammospheres. Imaging revealed unique metabolic phenotypes across the stages of tumor development. Although primary mammospheres overexpressing Her2 maintained increased glucose uptake ("Warburg effect"), after Her2 downregulation, during regression and residual disease, mammospheres appeared to switch to oxidative phosphorylation. Interestingly, in mammospheres where Her2 overexpression was turned back on to model recurrence, glucose uptake was lowest, indicating a potential change in substrate preference following the reactivation of Her2, reeliciting growth. Our findings highlight the importance of imaging metabolic adaptions to gain insight into the fundamental behaviors of residual and recurrent disease. IMPLICATIONS: This study demonstrates these functional fluorescent probes' ability to report metabolic adaptations during primary tumor growth, regression, residual disease, and regrowth in Her2 breast tumors.
Authors
Madonna, MC; Fox, DB; Crouch, BT; Lee, J; Zhu, C; Martinez, AF; Alvarez, JV; Ramanujam, N
MLA Citation
Madonna, Megan C., et al. “Optical Imaging of Glucose Uptake and Mitochondrial Membrane Potential to Characterize Her2 Breast Tumor Metabolic Phenotypes.Mol Cancer Res, vol. 17, no. 7, July 2019, pp. 1545–55. Pubmed, doi:10.1158/1541-7786.MCR-18-0618.
URI
https://scholars.duke.edu/individual/pub1375682
PMID
30902832
Source
pubmed
Published In
Mol Cancer Res
Volume
17
Published Date
Start Page
1545
End Page
1555
DOI
10.1158/1541-7786.MCR-18-0618

Clonal dynamics during breast cancer dormancy and recurrence.

Authors
Damrauer, J; Alvarez, JV
MLA Citation
Damrauer, Jeffrey, and James V. Alvarez. “Clonal dynamics during breast cancer dormancy and recurrence.Cancer Research, vol. 78, no. 10, AMER ASSOC CANCER RESEARCH, 2018, pp. 27–28.
URI
https://scholars.duke.edu/individual/pub1319716
Source
wos
Published In
Cancer Research
Volume
78
Published Date
Start Page
27
End Page
28

Isolation of unique STAT5 targets by chromatin immunoprecipitation-based gene identification.

STAT5a and STAT5b are two highly related transcription factors that control essential cellular functions. Several STAT5 targets are known, although it is likely that most remain uncharacterized. To identify a more complete set of STAT5-regulated genes, we used a modification of the chromatin immunoprecipitation procedure, which does not presuppose any information regarding these targets. Employing Ba/f3 cells in which STAT5 is activated by interleukin-3, we have identified novel STAT5 binding sites that may be regulatory regions for nearby genes. These sites are typically found far from transcription start sites, and most do not contain CpG islands, indicating that they are not in traditional promoter regions. Nonetheless, when the expression of genes near these STAT5 binding sites was examined, all were expressed in Ba/f3 cells, and most were modulated by interleukin-3. Furthermore, genes identified by this strategy show unique expression patterns in acute leukemias, tumors characterized by activated STAT5. Whereas both STAT5 isoforms bound to all promoters tested, STAT5a and STAT5b bound with different kinetics, suggesting that at least some of the differences between the functions of these two proteins are mediated by their DNA binding activity. Therefore, this method of transcription factor target identification represents an effective strategy to isolate transcription factor targets in an unbiased fashion, and it has revealed many novel STAT5-dependent regulatory regions outside of traditional promoters.
Authors
Nelson, EA; Walker, SR; Alvarez, JV; Frank, DA
MLA Citation
Nelson, Erik A., et al. “Isolation of unique STAT5 targets by chromatin immunoprecipitation-based gene identification.J Biol Chem, vol. 279, no. 52, Dec. 2004, pp. 54724–30. Pubmed, doi:10.1074/jbc.M408464200.
URI
https://scholars.duke.edu/individual/pub1116161
PMID
15498775
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
279
Published Date
Start Page
54724
End Page
54730
DOI
10.1074/jbc.M408464200

Foxo-dependent Par-4 Upregulation Prevents Long-term Survival of Residual Cells Following PI3K-Akt Inhibition.

Tumor recurrence is a leading cause of death and is thought to arise from a population of residual cells that survive treatment. These residual cancer cells can persist, locally or at distant sites, for years or decades. Therefore, understanding the pathways that regulate residual cancer cell survival may suggest opportunities for targeting these cells to prevent recurrence. Previously, it was observed that the proapoptotic protein (PAWR/Par-4) negatively regulates residual cell survival and recurrence in mice and humans. However, the mechanistic underpinnings on how Par-4 expression is regulated are unclear. Here, it is demonstrated that Par-4 is transcriptionally upregulated following treatment with multiple drugs targeting the PI3K-Akt-mTOR signaling pathway, and identify the Forkhead family of transcription factors as mediators of this upregulation. Mechanistically, Foxo3a directly binds to the Par-4 promoter and activates its transcription following inhibition of the PI3K-Akt pathway. This Foxo-dependent Par-4 upregulation limits the long-term survival of residual cells following treatment with therapeutics that target the PI3K-Akt pathway. Taken together, these results indicate that residual breast cancer tumor cell survival and recurrence requires circumventing Foxo-driven Par-4 upregulation and suggest that approaches to enforce Par-4 expression may prevent residual cell survival and recurrence. Mol Cancer Res; 16(4); 599-609. ©2018 AACR.
Authors
Damrauer, JS; Phelps, SN; Amuchastegui, K; Lupo, R; Mabe, NW; Walens, A; Kroger, BR; Alvarez, JV
MLA Citation
Damrauer, Jeffrey S., et al. “Foxo-dependent Par-4 Upregulation Prevents Long-term Survival of Residual Cells Following PI3K-Akt Inhibition.Mol Cancer Res, vol. 16, no. 4, Apr. 2018, pp. 599–609. Pubmed, doi:10.1158/1541-7786.MCR-17-0492.
URI
https://scholars.duke.edu/individual/pub1296901
PMID
29330285
Source
pubmed
Published In
Mol Cancer Res
Volume
16
Published Date
Start Page
599
End Page
609
DOI
10.1158/1541-7786.MCR-17-0492