James Alvarez

Positions:

Adjunct Assistant Professor in the Department 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:

Awakening the dormant tumor: the role of the tumor microenvironment in breast cancer recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Sponsor
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

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

The role of NRF2 in breast cancer dormancy and recurrence

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

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

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

Publications:

Context-dependent effects of whole-genome duplication during mammary tumor recurrence.

Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.
Authors
Newcomb, R; Dean, E; McKinney, BJ; Alvarez, JV
MLA Citation
Newcomb, Rachel, et al. “Context-dependent effects of whole-genome duplication during mammary tumor recurrence.Sci Rep, vol. 11, no. 1, July 2021, p. 14932. Pubmed, doi:10.1038/s41598-021-94332-z.
URI
https://scholars.duke.edu/individual/pub1489965
PMID
34294755
Source
pubmed
Published In
Scientific Reports
Volume
11
Published Date
Start Page
14932
DOI
10.1038/s41598-021-94332-z

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