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:

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

Oncogene addiction: Mouse models and clinical relevance for molecularly targeted therapies

© 2012, Springer Science+Business Media, LLC. All rights reserved. Cancer results from the dysregulation of pathways controlling the growth, proliferation, differentiation, and survival of tumor cells, as well as fundamental alterations in the manner in which cells interact with their microenvironment (Hanahan and Weinberg 2000). Several lines of evidence suggest that these alterations are due to the accumulation of multiple mutations in oncogenes and tumor suppressor genes that disrupt their normal function or regulation. These mutations provide a selective advantage to the cells in which they occur, leading to their expansion and clinical manifestation as a tumor.
Authors
Alvarez, JV; Yeh, ES; Feng, Y; Chodosh, LA
MLA Citation
Alvarez, J. V., et al. Oncogene addiction: Mouse models and clinical relevance for molecularly targeted therapies. Jan. 2012, pp. 527–47. Scopus, doi:10.1007/978-0-387-69805-2_25.
URI
https://scholars.duke.edu/individual/pub1116151
Source
scopus
Published Date
Start Page
527
End Page
547
DOI
10.1007/978-0-387-69805-2_25

Akt is required for Stat5 activation and mammary differentiation.

INTRODUCTION: The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1, but not Akt2, exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1-deficient and Akt2-deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation. METHODS: In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1-deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and Akt2 and determined the effect on mammary differentiation during pregnancy and lactation. RESULTS: Deletion of one allele of Akt2 in Akt1-deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near-complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1(-/-);Akt2(+/-) mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2. CONCLUSIONS: Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation.
Authors
Chen, C-C; Boxer, RB; Stairs, DB; Portocarrero, CP; Horton, RH; Alvarez, JV; Birnbaum, MJ; Chodosh, LA
MLA Citation
Chen, Chien-Chung, et al. “Akt is required for Stat5 activation and mammary differentiation..” Breast Cancer Res, vol. 12, no. 5, 2010. Pubmed, doi:10.1186/bcr2640.
URI
https://scholars.duke.edu/individual/pub1116152
PMID
20849614
Source
pubmed
Published In
Breast Cancer Res
Volume
12
Published Date
Start Page
R72
DOI
10.1186/bcr2640

Akt is required for Stat5 activation and mammary differentiation.

The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1, but not Akt2, exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1-deficient and Akt2-deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation. In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1-deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and Akt2 and determined the effect on mammary differentiation during pregnancy and lactation. Deletion of one allele of Akt2 in Akt1-deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near-complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1(-/-);Akt2(+/-) mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2. Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation.
Authors
Chen, C-C; Boxer, RB; Stairs, DB; Portocarrero, CP; Horton, RH; Alvarez, JV; Birnbaum, MJ; Chodosh, LA
MLA Citation
Chen, C. .. C., et al. “Akt is required for Stat5 activation and mammary differentiation..” Breast Cancer Research : Bcr, vol. 12, no. 5, 2010. Scival, doi:10.1186/bcr2640.
URI
https://scholars.duke.edu/individual/pub1116153
Source
scival
Published In
Breast Cancer Res
Volume
12
Published Date
Start Page
R72
DOI
10.1186/bcr2640

Singular value decomposition-based regression identifies activation of endogenous signaling pathways in vivo.

The ability to detect activation of signaling pathways based solely on gene expression data represents an important goal in biological research. We tested the sensitivity of singular value decomposition-based regression by focusing on functional interactions between the Ras and transforming growth factor beta signaling pathways. Our findings demonstrate that this approach is sufficiently sensitive to detect the secondary activation of endogenous signaling pathways as it occurs through crosstalk following ectopic activation of a primary pathway.
Authors
Liu, Z; Wang, M; Alvarez, JV; Bonney, ME; Chen, C-C; D'Cruz, C; Pan, T-C; Tadesse, MG; Chodosh, LA
MLA Citation
Liu, Zhandong, et al. “Singular value decomposition-based regression identifies activation of endogenous signaling pathways in vivo..” Genome Biol, vol. 9, no. 12, 2008. Pubmed, doi:10.1186/gb-2008-9-12-r180.
URI
https://scholars.duke.edu/individual/pub1116154
PMID
19094238
Source
pubmed
Published In
Genome Biology
Volume
9
Published Date
Start Page
R180
DOI
10.1186/gb-2008-9-12-r180