Jennifer Yunyan Zhang

Overview:

Epidermis of the skin constitutes the largest organ and the outer most barrier of the body. It is one of the few organs that undergo lifelong self-renewal through a tight balance of cell growth, differentiation, and programmed cell death. Deregulation of this balance is manifested in many diseases, including various immune diseases and cancer. 

Our lab is focused on 3 interrelated topics:

1. Gene regulation of epithelial cell proliferation and differentiation

Using regenerated human skin tissues and murine genetic models, we have demonstrated important functions NF-kB and AP-1 gene regulators in epidermal cell growth and differentiation. Currently, our efforts are focused on understating how loss-of-function of CYLD, a deubiquitinase and tumor suppressor, leads to the development of hair follicle defects, skin inflammation, and cancer. Specifically, we want to determine how CYLD integrates NF-kB, AP1, Myc, and other transcription factors to control epidermal cell growth and lineage differentiation.

De novo skin regeneration is life-saving procedure for severely burned patients and lethal genetic skin diseases such as epidermal bullosa. An additional aspect of our study is to improve new skin regeneration techniques and to create experimental skin disease models with gene transduced keratinocytes, as illustrated below.

2. Keratinocytes as instigators of inflammatory responses

Keratinocytes are constantly challenged by external insults, as well as immune cells. Disarray of the crosstalk between keratinocytes and immune cells underlies various immune diseases, including dermatitis, psoriasis, and cutaneous graft-versus-host disease (GVHD). GVHD is a common complication and the leading cause of non-relapse mortality among patients after receiving allogenic hematopoietic stem cell transplantation.  The skin is the most commonly affected organ in both the acute and chronic forms of this disease.  Treatment options for GVHD are limited and the current standard therapy is high dose systemic corticosteroid which is itself associated with significant morbidity. Our goal is to understand how keratinocytes contribute to the progression of GVHD, and may therefore be targeted to mitigate the disease.

3. Ubiquitination enzymes in melanoma

Melanoma most lethal and difficult to treat skin cancer. In the recent years, BRAF/MEK-targeted therapies have produced exciting results, but they suffer from short duration. Our goal is to uncover novel mechanisms crucial for melanoma malignancy. Specifically, we want to understand how ubiquitination enzymes contribute to melanoma growth. Previously, we have demonstrated that CYLD inhibits melanoma growth through suppression of JNK/AP1 and b1-integrin signaling pathways. In contrast, UBE2N, a K63-Ubiquitin conjusage, promotes melanoma growth in part through activation of the MEK/FRA/SOX10 signaling cascade. Currently, our efforts are focused on understanding how UBE2N and other ubiquitin enzymes regulate the MAPK signaling pathway and whether they can be targeted for melanoma therapy.

Positions:

Associate Professor in Dermatology

Dermatology
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

B.S. 1990

Nankai University (China)

Ph.D. 1998

University of Florida

Postdoctoral Fellow, Molecular And Cellular Biology, Immunology

University of California, School of Medicine

Postdoctoral Associate, Molecular And Cellular Biology, Cancer Biology

Stanford University, School of Medicine

Grants:

JUN PROTEINS IN EPIDERMAL HOMEOSTASIS AND NEOPLASIA

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Pilot Study Evaluating the Efficacy of a Topical PDE-4 Inhibitor for Morphea

Administered By
Dermatology
Awarded By
Pfizer, Inc.
Role
Co-Principal Investigator
Start Date
End Date

NF-kB, CDK4 and JNK in Epidermal Growth Regulation

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Improving Melanoma Diagnosis with Pump-Probe Optical Imaging

Administered By
Chemistry
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Imaging Nonlinear Absorption of Biomarkers for Improved Detection of Melanoma

Administered By
Chemistry
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

Publications:

Potential Utility of Synthetic D-Lactate Polymers in Skin Cancer

Authors
Dikshit, A; Lu, J; Ford, AE; Degan, S; Jin, YJ; Sun, H; Nichols, A; Salama, AKS; Beasley, G; Gooden, D; Zhang, JY
MLA Citation
Dikshit, Anushka, et al. “Potential Utility of Synthetic D-Lactate Polymers in Skin Cancer.” Jid Innovations, vol. 1, no. 3, Elsevier BV, Sept. 2021, pp. 100043–100043. Crossref, doi:10.1016/j.xjidi.2021.100043.
URI
https://scholars.duke.edu/individual/pub1494974
Source
crossref
Published In
Jid Innovations
Volume
1
Published Date
Start Page
100043
End Page
100043
DOI
10.1016/j.xjidi.2021.100043

Novel light-driven functional AgNPs induce cancer death at extra low concentrations.

The current study is aimed at preparing light-driven novel functional AgNPs- bio-hydrogel and evaluating anticancer potency against human melanoma cells. With an average size of 16-18 nm, the hydrogel nano-silver particle composite (AgNPs@C_MA_O) was synthesized using a soft white LED approach and analyzed by UV-Vis, DLS, FTIR, X-ray, SEM-EDX and TEM techniques. The anticancer activity of the obtained novel functionalized AgNPs@C_MA_O was tested in-vitro in the A375 melanoma cell line. Dose-response analysis showed that AgNPs at 0.01 mg/mL and 0.005 mg/mL doses reduced the viability of A375 cells by 50% at 24 and 48-h time-points, respectively. A375 cells treated with AgNPs@C_MA_O for 24 h at IC50 displayed abnormal morphology such as detachment edges and feet, shrinkage, membrane damage, and the loss of contact with adjacent cells. Our work is the first study showing that non-ionizing radiation mediated biofunctionalized AgNPs have an anti-tumoral effect at such a low concentration of 0.01 mg/mL. Our approach of using harmless wLED increased synergy between soft biopolymer compounds and AgNPs, and enhanced anticancer efficiency of the AgNPs@C_MA_O biohydrogel. Ultimately, the AgNPs accessed through the use of the wLED approach in colloidal syntheses can open new applications and combinatorial advanced cancer treatments and diagnostics.
Authors
Bunyatova, U; Hammouda, MB; Zhang, J
MLA Citation
Bunyatova, Ulviye, et al. “Novel light-driven functional AgNPs induce cancer death at extra low concentrations.Scientific Reports, vol. 11, no. 1, June 2021, p. 13258. Epmc, doi:10.1038/s41598-021-92689-9.
URI
https://scholars.duke.edu/individual/pub1487824
PMID
34168242
Source
epmc
Published In
Scientific Reports
Volume
11
Published Date
Start Page
13258
DOI
10.1038/s41598-021-92689-9

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent abscesses, nodules, and sinus tracts in areas of high hair follicle and sweat gland density. These sinus tracts can present with purulent drainage and scar formation. Dysregulation of multiple immune pathways drives the complexity of HS pathogenesis and may account for the heterogeneity of treatment response in HS patients. Using transcriptomic approaches, including single-cell sequencing and protein analysis, we here characterize the innate inflammatory landscape of HS lesions. We identified a shared upregulation of genes involved in interferon (IFN) and antimicrobial defense signaling through transcriptomic overlap analysis of differentially expressed genes (DEGs) in datasets from HS skin, diabetic foot ulcers (DFUs), and the inflammatory stage of normal healing wounds. Overlap analysis between HS- and DFU-specific DEGs revealed an enrichment of gene signatures associated with monocyte/macrophage functions. Single-cell RNA sequencing further revealed monocytes/macrophages with polarization toward a pro-inflammatory M1-like phenotype and increased effector function, including antiviral immunity, phagocytosis, respiratory burst, and antibody-dependent cellular cytotoxicity. Specifically, we identified the STAT1/IFN-signaling axis and the associated IFN-stimulated genes as central players in monocyte/macrophage dysregulation. Our data indicate that monocytes/macrophages are a potential pivotal player in HS pathogenesis and their pathways may serve as therapeutic targets and biomarkers in HS treatment.
Authors
Mariottoni, P; Jiang, SW; Prestwood, CA; Jain, V; Suwanpradid, J; Whitley, MJ; Coates, M; Brown, DA; Erdmann, D; Corcoran, DL; Gregory, SG; Jaleel, T; Zhang, JY; Harris-Tryon, TA; MacLeod, AS
MLA Citation
Mariottoni, Paula, et al. “Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa.Front Med (Lausanne), vol. 8, 2021, p. 665873. Pubmed, doi:10.3389/fmed.2021.665873.
URI
https://scholars.duke.edu/individual/pub1496054
PMID
34504848
Source
pubmed
Published In
Frontiers in Medicine
Volume
8
Published Date
Start Page
665873
DOI
10.3389/fmed.2021.665873

The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer.

The c-Jun N-terminal kinases (JNKs), with its members JNK1, JNK2, and JNK3, is a subfamily of (MAPK) mitogen-activated protein kinases. JNK signaling regulates a wide range of cellular processes, including cell proliferation, differentiation, survival, apoptosis, and inflammation. Dysregulation of JNK pathway is associated with a wide range of immune disorders and cancer. Our objective is to provide a review of JNK proteins and their upstream regulators and downstream effector molecules in common skin disorders, including psoriasis, dermal fibrosis, scleroderma, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma.
Authors
Hammouda, MB; Ford, AE; Liu, Y; Zhang, JY
MLA Citation
Hammouda, Manel B., et al. “The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer.Cells, vol. 9, no. 4, Apr. 2020. Pubmed, doi:10.3390/cells9040857.
URI
https://scholars.duke.edu/individual/pub1437028
PMID
32252279
Source
pubmed
Published In
Cells
Volume
9
Published Date
DOI
10.3390/cells9040857

ENTPD1 (CD39) Expression Inhibits UVR-Induced DNA Damage Repair through Purinergic Signaling and Is Associated with Metastasis in Human Cutaneous Squamous Cell Carcinoma.

UVR and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells promote cSCC carcinogenesis, and in other solid tumors, infiltrating regulatory T cells and CD8+ T cells express ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39), an ectoenzyme that catalyzes the rate-limiting step in converting extracellular adenosine triphosphate (ATP) to extracellular adenosine (ADO). We previously showed that extracellular purine nucleotides influence DNA damage repair. In this study, we investigate whether DNA damage repair is modulated through purinergic signaling in cSCC. We found increased ENTPD1 expression on T cells within cSCCs when compared with the expression on T cells from blood or nonlesional skin, and accordingly, concentrations of derivative extracellular adenosine diphosphate (ADP), adenosine monophosphate (AMP), and ADO are increased in tumors compared with those in normal skin. Importantly, ENTPD1 expression is significantly higher in human cSCCs that metastasize than in those that are nonmetastatic. We also identify in a mouse model that ENTPD1 expression is induced by UVR in an IL-27-dependent manner. Finally, increased extracellular ADO is shown to downregulate the expression of NAP1L2, a nucleosome assembly protein we show to be important for DNA damage repair secondary to UVR. Together, these data suggest a role for ENTPD1 expression on skin-resident T cells to regulate DNA damage repair through purinergic signaling to promote skin carcinogenesis and metastasis.
Authors
Whitley, MJ; Suwanpradid, J; Lai, C; Jiang, SW; Cook, JL; Zelac, DE; Rudolph, R; Corcoran, DL; Degan, S; Spasojevic, I; Levinson, H; Erdmann, D; Reid, C; Zhang, JY; Robson, SC; Healy, E; Havran, WL; MacLeod, AS
MLA Citation
Whitley, Melodi Javid, et al. “ENTPD1 (CD39) Expression Inhibits UVR-Induced DNA Damage Repair through Purinergic Signaling and Is Associated with Metastasis in Human Cutaneous Squamous Cell Carcinoma.J Invest Dermatol, vol. 141, no. 10, Oct. 2021, pp. 2509–20. Pubmed, doi:10.1016/j.jid.2021.02.753.
URI
https://scholars.duke.edu/individual/pub1478127
PMID
33848530
Source
pubmed
Published In
J Invest Dermatol
Volume
141
Published Date
Start Page
2509
End Page
2520
DOI
10.1016/j.jid.2021.02.753