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

CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors.

Over half of breast-cancer-related deaths are due to recurrence 5 or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.
Authors
Walens, A; DiMarco, AV; Lupo, R; Kroger, BR; Damrauer, JS; Alvarez, JV
MLA Citation
Walens, Andrea, et al. “CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors..” Elife, vol. 8, Apr. 2019. Pubmed, doi:10.7554/eLife.43653.
URI
https://scholars.duke.edu/individual/pub1381387
PMID
30990165
Source
pubmed
Published In
Elife
Volume
8
Published Date
DOI
10.7554/eLife.43653

Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor.

Somatic mutations in the epidermal growth factor receptor (EGFR) occur frequently in lung cancer and confer sensitivity to EGFR kinase inhibitors gefitinib and erlotinib. These mutations, which occur in the kinase domain of the protein, also render EGFR constitutively active and transforming. Signal transducers and activators of transcription 3 (STAT3) transduces signals from a number of oncogenic tyrosine kinases and contributes to a wide spectrum of human malignancies. Here, we show that STAT3 is activated by mutant EGFRs and is necessary for its downstream phenotypic effects. Inhibiting STAT3 function in fibroblasts abrogates transformation by mutant EGFR. In non-small-cell lung cancer cells, STAT3 activity is regulated by EGFR through modulation of STAT3 serine phosphorylation. Inhibiting STAT3 function increases apoptosis of these cells, suggesting that STAT3 is necessary for their survival. Finally, a group of genes constituting a STAT3 signature is enriched in lung tumors with EGFR mutations. Thus, STAT3 is a critical mediator of the oncogenic effects of somatic EGFR mutations and targeting STAT3 may be an effective strategy for treating tumors characterized by these mutations.
Authors
Alvarez, JV; Greulich, H; Sellers, WR; Meyerson, M; Frank, DA
MLA Citation
Alvarez, James V., et al. “Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor..” Cancer Res, vol. 66, no. 6, Mar. 2006, pp. 3162–68. Pubmed, doi:10.1158/0008-5472.CAN-05-3757.
URI
https://scholars.duke.edu/individual/pub1116157
PMID
16540667
Source
pubmed
Published In
Cancer Research
Volume
66
Published Date
Start Page
3162
End Page
3168
DOI
10.1158/0008-5472.CAN-05-3757

bcSeq: an R package for fast sequence mapping in high-throughput shRNA and CRISPR screens.

Summary: CRISPR-Cas9 and shRNA high-throughput sequencing screens have abundant applications for basic and translational research. Methods and tools for the analysis of these screens must properly account for sequencing error, resolve ambiguous mappings among similar sequences in the barcode library in a statistically principled manner, and be computationally efficient. Herein we present bcSeq, an open source R package that implements a fast and parallelized algorithm for mapping high-throughput sequencing reads to a barcode library while tolerating sequencing error. The algorithm uses a Trie data structure for speed and resolves ambiguous mappings by using a statistical sequencing error model based on Phred scores for each read. Availability and implementation: The package source code and an accompanying tutorial are available at http://bioconductor.org/packages/bcSeq/. Supplementary information: Supplementary data are available at Bioinformatics online.
Authors
Lin, J; Gresham, J; Wang, T; Kim, SY; Alvarez, J; Damrauer, JS; Floyd, S; Granek, J; Allen, A; Chan, C; Xie, J; Owzar, K
MLA Citation
Lin, Jiaxing, et al. “bcSeq: an R package for fast sequence mapping in high-throughput shRNA and CRISPR screens..” Bioinformatics, vol. 34, no. 20, Oct. 2018, pp. 3581–83. Pubmed, doi:10.1093/bioinformatics/bty402.
URI
https://scholars.duke.edu/individual/pub1319456
PMID
29790906
Source
pubmed
Published In
Bioinformatics
Volume
34
Published Date
Start Page
3581
End Page
3583
DOI
10.1093/bioinformatics/bty402

Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.

BACKGROUND: Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described. METHODS AND FINDINGS: Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785. CONCLUSION: Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies.
Authors
Greulich, H; Chen, T-H; Feng, W; Jänne, PA; Alvarez, JV; Zappaterra, M; Bulmer, SE; Frank, DA; Hahn, WC; Sellers, WR; Meyerson, M
MLA Citation
Greulich, Heidi, et al. “Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants..” Plos Med, vol. 2, no. 11, Nov. 2005. Pubmed, doi:10.1371/journal.pmed.0020313.
URI
https://scholars.duke.edu/individual/pub1116159
PMID
16187797
Source
pubmed
Published In
Plos Medicine
Volume
2
Published Date
Start Page
e313
DOI
10.1371/journal.pmed.0020313