Zachary Hartman

Overview:

My research interests encompass studies of immunity and inflammation in the context of developing and established cancers. These research interests involve studies of inflammation in the genesis and maintenance of specific cancer types (principally breast and ovarian), as well as the impact of inflammation on tumor metastasis and the tumor microenvironment.  My group is also involved in strategies to modulate the immune response to tumors, which involves the use of novel immunotherapeutic strategies and development of vaccines to specific oncogenic targets.  The major focus of my lab is in uncovering strategies to modulate tumor-derived inflammation and tumor-specific immunity that will translate into clinically efficacious therapies in patients.

Positions:

Assistant Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Assistant Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2006

Duke University

Post-Doctoral Fellow

Duke University

Post Doctoral Fellow, Md Anderson Cancer Center

University of Texas Medical School at Houston

Grants:

A Neoepitope Subunit Vaccine Targeting the Mutated Estrogen Receptor Ligand Binding Domain to Treat and Prevent Endocrine Resistant ER+ Breast Cancer

Administered By
Surgery, Surgical Sciences
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Study of LAMP Vaccines in HER2+ Breast Cancer

Administered By
Surgery, Surgical Sciences
Role
Principal Investigator
Start Date
End Date

Investigation of stimulating stress response mechanisms to enhance antibody dependent cellular phagocytosis

Administered By
Surgery, Surgical Sciences
Role
Principal Investigator
Start Date
End Date

Publications:

IL-26, a non-canonical mediator of DNA inflammatory stimulation, promotes TNBC engraftment and progression in association with neutrophils.

Interleukin-26 (IL-26) is a unique amphipathic member of the IL-10 family of cytokines that participates in inflammatory signaling through a canonical receptor pathway. It also directly binds DNA to facilitate cellular transduction and intracellular inflammatory signaling. While IL-26 has almost no described role in cancer, our in vivo screen of inflammatory and cytokine pathway genes revealed IL-26 to be one of the most significant inflammatory mediators of mammary engraftment and lung metastatic growth in triple-negative breast cancer (TNBC). Examination of human breast cancers demonstrated elevated IL-26 transcripts in TNBC specimens, specifically in tumor cells as well as in Th17 CD4+ T-cells within clinical TNBC specimens. IL-26 did not have an autocrine effect on human TNBC cells, but rather its effect on engraftment and growth in vivo required neutrophils. IL-26 enhanced mouse-derived DNA induction of inflammatory cytokines, which were collectively important for mammary and metastatic lung engraftment. To neutralize this effect, we developed a novel IL-26 vaccine to stimulate antibody production and suppress IL-26 enhanced engraftment in vivo, suggesting that targeting this inflammatory amplifier could be a unique means to control cancer-promoting inflammation in TNBC and other autoimmune diseases. Thus, we identified IL-26 as a novel key modulator of TNBC metastasis and a potential therapeutic target in TNBC as well as other diseases reliant upon IL-26-mediated inflammatory stimulation.
Authors
Trotter, TN; Shuptrine, CW; Tsao, L-C; Marek, RD; Acharya, C; Wei, J-P; Yang, X-Y; Lei, G; Wang, T; Lyerly, HK; Hartman, ZC
MLA Citation
Trotter, Timothy N., et al. “IL-26, a non-canonical mediator of DNA inflammatory stimulation, promotes TNBC engraftment and progression in association with neutrophils.Cancer Res, May 2020. Pubmed, doi:10.1158/0008-5472.CAN-18-3825.
URI
https://scholars.duke.edu/individual/pub1439660
PMID
32366475
Source
pubmed
Published In
Cancer Res
Published Date
DOI
10.1158/0008-5472.CAN-18-3825

The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment.

Amplification and overexpression of erbB2/neu proto-oncogene is observed in 20-30% human breast cancer and is inversely correlated with the survival of the patient. Despite this, somatic activating mutations within erbB2 in human breast cancers are rare. However, we have previously reported that a splice isoform of erbB2, containing an in-frame deletion of exon 16 (herein referred to as ErbB2ΔEx16), results in oncogenic activation of erbB2 because of constitutive dimerization of the ErbB2 receptor. Here, we demonstrate that the ErbB2ΔEx16 is a major oncogenic driver in breast cancer that constitutively signals from the cell surface. We further show that inducible expression of the ErbB2ΔEx16 variant in mammary gland of transgenic mice results in the rapid development of metastatic multifocal mammary tumors. Genetic and biochemical characterization of the ErbB2ΔEx16-derived mammary tumors exhibit several unique features that distinguish this model from the conventional ErbB2 ones expressing the erbB2 proto-oncogene in mammary epithelium. Unlike the wild-type ErbB2-derived tumors that express luminal keratins, ErbB2ΔEx16-derived tumors exhibit high degree of intratumoral heterogeneity co-expressing both basal and luminal keratins. Consistent with these distinct pathological features, the ErbB2ΔEx16 tumors exhibit distinct signaling and gene expression profiles that correlate with activation of number of key transcription factors implicated in breast cancer metastasis and cancer stem cell renewal.
Authors
Turpin, J; Ling, C; Crosby, EJ; Hartman, ZC; Simond, AM; Chodosh, LA; Rennhack, JP; Andrechek, ER; Ozcelik, J; Hallett, M; Mills, GB; Cardiff, RD; Gray, JW; Griffith, OL; Muller, WJ
MLA Citation
Turpin, J., et al. “The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment.Oncogene, vol. 35, no. 47, Nov. 2016, pp. 6053–64. Pubmed, doi:10.1038/onc.2016.129.
URI
https://scholars.duke.edu/individual/pub1132336
PMID
27157621
Source
pubmed
Published In
Oncogene
Volume
35
Published Date
Start Page
6053
End Page
6064
DOI
10.1038/onc.2016.129

Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.

Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-negative" breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells.
Authors
Mazumdar, A; Poage, GM; Shepherd, J; Tsimelzon, A; Hartman, ZC; Den Hollander, P; Hill, J; Zhang, Y; Chang, J; Hilsenbeck, SG; Fuqua, S; Kent Osborne, C; Mills, GB; Brown, PH
MLA Citation
Mazumdar, Abhijit, et al. “Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.Breast Cancer Research and Treatment, vol. 158, no. 3, Aug. 2016, pp. 441–54. Epmc, doi:10.1007/s10549-016-3892-y.
URI
https://scholars.duke.edu/individual/pub1167171
PMID
27393618
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
158
Published Date
Start Page
441
End Page
454
DOI
10.1007/s10549-016-3892-y

Death-associated protein kinase 1 promotes growth of p53-mutant cancers.

Estrogen receptor-negative (ER-negative) breast cancers are extremely aggressive and associated with poor prognosis. In particular, effective treatment strategies are limited for patients diagnosed with triple receptor-negative breast cancer (TNBC), which also carries the worst prognosis of all forms of breast cancer; therefore, extensive studies have focused on the identification of molecularly targeted therapies for this tumor subtype. Here, we sought to identify molecular targets that are capable of suppressing tumorigenesis in TNBCs. Specifically, we found that death-associated protein kinase 1 (DAPK1) is essential for growth of p53-mutant cancers, which account for over 80% of TNBCs. Depletion or inhibition of DAPK1 suppressed growth of p53-mutant but not p53-WT breast cancer cells. Moreover, DAPK1 inhibition limited growth of other p53-mutant cancers, including pancreatic and ovarian cancers. DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTOR pathway. Our studies demonstrated that high DAPK1 expression causes increased cancer cell growth and enhanced signaling through the mTOR/S6K pathway; evaluation of multiple breast cancer patient data sets revealed that high DAPK1 expression associates with worse outcomes in individuals with p53-mutant cancers. Together, our data support targeting DAPK1 as a potential therapeutic strategy for p53-mutant cancers.
Authors
Zhao, J; Zhao, D; Poage, GM; Mazumdar, A; Zhang, Y; Hill, JL; Hartman, ZC; Savage, MI; Mills, GB; Brown, PH
MLA Citation
Zhao, Jing, et al. “Death-associated protein kinase 1 promotes growth of p53-mutant cancers.J Clin Invest, vol. 125, no. 7, July 2015, pp. 2707–20. Pubmed, doi:10.1172/JCI70805.
URI
https://scholars.duke.edu/individual/pub1081781
PMID
26075823
Source
pubmed
Published In
J Clin Invest
Volume
125
Published Date
Start Page
2707
End Page
2720
DOI
10.1172/JCI70805

Novel adenovirus vectors 'capsid-displaying' a human complement inhibitor.

Adenovirus (Ad) vectors are currently the most commonly utilized gene transfer vectors in humans worldwide. Unfortunately, upon contact with the circulatory system, Ads induce several, innate, complement-dependent toxicities that limit the full potential for Ad-based gene transfer applications. Therefore, we have constructed several novel Ad5-based vectors, 'capsid-displaying' as fiber or pIX fusion proteins, a complement-regulatory peptide (COMPinh). These novel Ads dramatically minimize Ad-dependent activation of the human and non-human primate complement systems, as determined by several assays. In summary, our work has shown that a novel COMPinh-displaying Ad5 has the potential for broadening the safe use of Ad vectors in future human applications.
Authors
Seregin, SS; Hartman, ZC; Appledorn, DM; Godbehere, S; Jiang, H; Frank, MM; Amalfitano, A
MLA Citation
Seregin, Sergey S., et al. “Novel adenovirus vectors 'capsid-displaying' a human complement inhibitor.J Innate Immun, vol. 2, no. 4, 2010, pp. 353–59. Pubmed, doi:10.1159/000284368.
URI
https://scholars.duke.edu/individual/pub771738
PMID
20375551
Source
pubmed
Published In
J Innate Immun
Volume
2
Published Date
Start Page
353
End Page
359
DOI
10.1159/000284368