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
Awarded By
American Cancer Society, Inc.
Role
Principal Investigator
Start Date
End Date

Defining the role of the histone methyltransferase G9a in mitigating replication stress in cancer

Awarded By
Howard Hughes Medical Institute
Role
Principal Investigator
Start Date
End Date

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

Publications:

DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway.

Recurrent breast cancer presents significant challenges with aggressive phenotypes and treatment resistance. Therefore, novel therapeutics are urgently needed. Here, we report that murine recurrent breast tumor cells, when compared with primary tumor cells, are highly sensitive to ferroptosis. Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), the receptor for collagen I, is highly expressed in ferroptosis-sensitive recurrent tumor cells and human mesenchymal breast cancer cells. EMT regulators, TWIST and SNAIL, significantly induce DDR2 expression and sensitize ferroptosis in a DDR2-dependent manner. Erastin treatment induces DDR2 upregulation and phosphorylation, independent of collagen I. Furthermore, DDR2 knockdown in recurrent tumor cells reduces clonogenic proliferation. Importantly, both the ferroptosis protection and reduced clonogenic growth may be compatible with the compromised YAP/TAZ upon DDR2 inhibition. Collectively, these findings identify the important role of EMT-driven DDR2 upregulation in recurrent tumors in maintaining growth advantage but activating YAP/TAZ-mediated ferroptosis susceptibility, providing potential strategies to eradicate recurrent breast cancer cells with mesenchymal features.
Authors
Lin, C-C; Yang, W-H; Lin, Y-T; Tang, X; Chen, P-H; Ding, C-KC; Qu, DC; Alvarez, JV; Chi, J-T
MLA Citation
Lin, Chao-Chieh, et al. “DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway.Oncogene, vol. 40, no. 11, Mar. 2021, pp. 2018–34. Pubmed, doi:10.1038/s41388-021-01676-x.
URI
https://scholars.duke.edu/individual/pub1474448
PMID
33603168
Source
pubmed
Published In
Oncogene
Volume
40
Published Date
Start Page
2018
End Page
2034
DOI
10.1038/s41388-021-01676-x

G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program.

Dysregulated gene expression is a common feature of cancer and may underlie some aspects of tumor progression, including tumor relapse. Here, we show that recurrent mammary tumors exhibit global changes in gene expression and histone modifications and acquire dependence on the G9a histone methyltransferase. Genetic ablation of G9a delays tumor recurrence, and pharmacologic inhibition of G9a slows the growth of recurrent tumors. Mechanistically, G9a activity is required to silence pro-inflammatory cytokines, including tumor necrosis factor (TNF), through H3K9 methylation at gene promoters. G9a inhibition induces re-expression of these cytokines, leading to p53 activation and necroptosis. Recurrent tumors upregulate receptor interacting protein kinase-3 (RIPK3) expression and are dependent upon RIPK3 activity. High RIPK3 expression renders recurrent tumors sensitive to necroptosis following G9a inhibition. These findings demonstrate that G9a-mediated silencing of pro-necroptotic proteins is a critical step in tumor recurrence and suggest that G9a is a targetable dependency in recurrent breast cancer.
Authors
Mabe, NW; Garcia, NMG; Wolery, SE; Newcomb, R; Meingasner, RC; Vilona, BA; Lupo, R; Lin, C-C; Chi, J-T; Alvarez, JV
MLA Citation
Mabe, Nathaniel W., et al. “G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program.Cell Rep, vol. 33, no. 5, Nov. 2020, p. 108341. Pubmed, doi:10.1016/j.celrep.2020.108341.
URI
https://scholars.duke.edu/individual/pub1464103
PMID
33147463
Source
pubmed
Published In
Cell Reports
Volume
33
Published Date
Start Page
108341
DOI
10.1016/j.celrep.2020.108341

Adaptation and selection shape clonal evolution of tumors during residual disease and recurrence.

The survival and recurrence of residual tumor cells following therapy constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during relapse. We use cellular barcoding to monitor clonal dynamics during tumor recurrence in vivo. We find that clonal diversity decreases during tumor regression, residual disease, and recurrence. The recurrence of dormant residual cells follows several distinct routes. Approximately half of the recurrent tumors exhibit clonal dominance with a small number of subclones comprising the vast majority of the tumor; these clonal recurrences are frequently dependent upon Met gene amplification. A second group of recurrent tumors comprises thousands of subclones, has a clonal architecture similar to primary tumors, and is dependent upon the Jak/Stat pathway. Thus the regrowth of dormant tumors proceeds via multiple routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities.
Authors
Walens, A; Lin, J; Damrauer, JS; McKinney, B; Lupo, R; Newcomb, R; Fox, DB; Mabe, NW; Gresham, J; Sheng, Z; Sibley, AB; De Buysscher, T; Kelkar, H; Mieczkowski, PA; Owzar, K; Alvarez, JV
MLA Citation
Walens, Andrea, et al. “Adaptation and selection shape clonal evolution of tumors during residual disease and recurrence.Nat Commun, vol. 11, no. 1, Oct. 2020, p. 5017. Pubmed, doi:10.1038/s41467-020-18730-z.
URI
https://scholars.duke.edu/individual/pub1462141
PMID
33024122
Source
pubmed
Published In
Nature Communications
Volume
11
Published Date
Start Page
5017
DOI
10.1038/s41467-020-18730-z

In vivo metabolic imaging reveals mitochondrial membrane potential reprogramming following Her2-targeted therapy and dormant disease

We performed in intravital fluorescent microscopy in a preclinical cancer dormancy model to capture key changes in mitochondrial activity associated with Her2 treated breast cancer both acutely and in a residual disease state.
Authors
Madonna, MC; Duer, J; Fox, D; Alvarez, J; Ramanujam, N
MLA Citation
Madonna, M. C., et al. “In vivo metabolic imaging reveals mitochondrial membrane potential reprogramming following Her2-targeted therapy and dormant disease.” Optics Infobase Conference Papers, vol. Part F178-Translational-2020, 2020.
URI
https://scholars.duke.edu/individual/pub1461801
Source
scopus
Published In
Optics Infobase Conference Papers
Volume
Part F178-Translational-2020
Published Date

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

The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation 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 breast cancer patients with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, while 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, Douglas B., et al. “NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.Nat Metab, vol. 2, no. 4, Apr. 2020, pp. 318–34. Pubmed, doi:10.1038/s42255-020-0191-z.
URI
https://scholars.duke.edu/individual/pub1437935
PMID
32691018
Source
pubmed
Published In
Nature Metabolism
Volume
2
Published Date
Start Page
318
End Page
334
DOI
10.1038/s42255-020-0191-z