Jung Wook Park

Positions:

Rollie Assistant Professorship of Correlative Pathology

Pathology
School of Medicine

Assistant Professor Track V in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2013

University of Wisconsin at Madison

Grants:

Unveiling the roles of neuroendocrine cells in prostate cancer development

Administered By
Pathology
Awarded By
Mike Slive Foundation
Role
Co-Principal Investigator
Start Date
End Date

Publications:

A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes.

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.
Authors
Wang, L; Smith, BA; Balanis, NG; Tsai, BL; Nguyen, K; Cheng, MW; Obusan, MB; Esedebe, FN; Patel, SJ; Zhang, H; Clark, PM; Sisk, AE; Said, JW; Huang, J; Graeber, TG; Witte, ON; Chin, AI; Park, JW
MLA Citation
Wang, Liang, et al. “A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes..” Proc Natl Acad Sci U S A, Dec. 2019. Pubmed, doi:10.1073/pnas.1915770117.
URI
https://scholars.duke.edu/individual/pub1424500
PMID
31871155
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Published Date
DOI
10.1073/pnas.1915770117

Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
Authors
Li, Y; He, Y; Butler, W; Xu, L; Chang, Y; Lei, K; Zhang, H; Zhou, Y; Gao, AC; Zhang, Q; Taylor, DG; Cheng, D; Farber-Katz, S; Karam, R; Landrith, T; Li, B; Wu, S; Hsuan, V; Yang, Q; Hu, H; Chen, X; Flowers, M; McCall, SJ; Lee, JK; Smith, BA; Park, JW; Goldstein, AS; Witte, ON; Wang, Q; Rettig, MB; Armstrong, AJ; Cheng, Q; Huang, J
MLA Citation
Li, Yanjing, et al. “Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer..” Sci Transl Med, vol. 11, no. 521, Dec. 2019. Pubmed, doi:10.1126/scitranslmed.aax0428.
URI
https://scholars.duke.edu/individual/pub1423084
PMID
31801883
Source
pubmed
Published In
Sci Transl Med
Volume
11
Published Date
DOI
10.1126/scitranslmed.aax0428

Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage

Authors
Park, JW; Nickel, KP; Torres, AD; Lee, D; Lambert, PF; Kimple, RJ
MLA Citation
Park, Jung Wook, et al. “Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage.” Radiotherapy and Oncology, vol. 113, no. 3, Elsevier BV, Dec. 2014, pp. 337–44. Crossref, doi:10.1016/j.radonc.2014.08.026.
URI
https://scholars.duke.edu/individual/pub1414265
Source
crossref
Published In
Radiotherapy and Oncology
Volume
113
Published Date
Start Page
337
End Page
344
DOI
10.1016/j.radonc.2014.08.026

Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice.

Cervical cancer is caused by human papillomavirus (HPV) in collaboration with other non-viral factors. The uterine cervix is hormone responsive and female hormones have been implicated in the pathogenesis of the disease. HPV transgenic mice expressing HPV16 oncogenes E6 (K14E6) and/or E7 (K14E7) have been employed to study a mechanism of estrogen and estrogen receptor α (ERα) in cervical carcinogenesis. A chronic exposure to physiological levels of exogenous estrogen leads to cervical cancer in the HPV transgenic mice, which depends on ERα. The receptor is composed of multiple functional domains including a DNA-binding domain (DBD), which mediates its binding to estrogen-responsive elements (EREs) on target genes. A transcriptional control of genes by ERα is mediated by either DBD-dependent (classical) or DBD-independent (non-classical) pathway. Although molecular mechanisms of ERα in cancer have been characterized extensively, studies investigating importance of each pathway for carcinogenesis are scarce. In this study, we employ knock-in mice expressing an ERα DBD mutant (E207A/G208A) that is defective specifically for ERE binding. We demonstrate that the ERα DBD mutant fails to support estrogen-induced epithelial cell proliferation and carcinogenesis in the cervix of K14E7 transgenic mice. We also demonstrate that cervical diseases are absent in K14E7 mice when one ERα DBD mutant allele and one wild-type allele are present. We conclude that the ERα classical pathway is required for cervical carcinogenesis in a mouse model.
Authors
Son, J; Park, JW; Lambert, PF; Chung, S-H
MLA Citation
Son, Jieun, et al. “Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice..” Carcinogenesis, vol. 35, no. 2, Feb. 2014, pp. 489–96. Pubmed, doi:10.1093/carcin/bgt350.
URI
https://scholars.duke.edu/individual/pub1411008
PMID
24148821
Source
pubmed
Published In
Carcinogenesis
Volume
35
Published Date
Start Page
489
End Page
496
DOI
10.1093/carcin/bgt350

High incidence of HPV-associated head and neck cancers in FA deficient mice is associated with E7's induction of DNA damage through its inactivation of pocket proteins.

Fanconi anemia (FA) patients are highly susceptible to solid tumors at multiple anatomical sites including head and neck region. A subset of head and neck cancers (HNCs) is associated with 'high-risk' HPVs, particularly HPV16. However, the correlation between HPV oncogenes and cancers in FA patients is still unclear. We previously learned that FA deficiency in mice predisposes HPV16 E7 transgenic mice to HNCs. To address HPV16 E6's oncogenic potential under FA deficiency in HNCs, we utilized HPV16 E6-transgenic mice (K14E6) and HPV16 E6/E7-bi-transgenic mice (K14E6E7) on genetic backgrounds sufficient or deficient for one of the fanc genes, fancD2 and monitored their susceptibility to HNCs. K14E6 mice failed to develop tumor. However, E6 and fancD2-deficiency accelerated E7-driven tumor development in K14E6E7 mice. The increased tumor incidence was more correlated with E7-driven DNA damage than proliferation. We also found that deficiency of pocket proteins, pRb, p107, and p130 that are well-established targets of E7, could recapitulate E7's induction of DNA damage. Our findings support the hypothesis that E7 induces HPV-associated HNCs by promoting DNA damage through the inactivation of pocket proteins, which explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. Our results further demonstrate the unexpected finding that FA deficiency does not predispose E6 transgenic mice to HNCs, indicating a specificity in the synergy between FA deficiency and HPV oncogenes in causing HNCs.
Authors
Park, JW; Shin, M-K; Pitot, HC; Lambert, PF
MLA Citation
URI
https://scholars.duke.edu/individual/pub1411009
PMID
24086435
Source
pubmed
Published In
Plos One
Volume
8
Published Date
Start Page
e75056
DOI
10.1371/journal.pone.0075056