Hailiang Hu

Positions:

Assistant Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2000

Shanghai Institute of Biochemistry, Chinese Academy of Sciences

Grants:

Targeting RNA splicing in race-related aggressive and lethal prostate cancer

Administered By
Duke Cancer Institute
Awarded By
Prostate Cancer Foundation
Role
Principal Investigator
Start Date
End Date

Role and targeting of PRMT5 in prostate cancer

Administered By
Pathology
Awarded By
Purdue University
Role
Principal Investigator
Start Date
End Date

A novel strategy to identify prostate cancer biomarkers for patient management

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

Stand Up 2 Cancer West Coast Dream Team Grant

Administered By
Pathology
Awarded By
University of San Francisco
Role
Principal Investigator
Start Date
End Date

Targeting Glutaminase Isoforms for Therapy-Resistant Prostate Cancer

Administered By
Pathology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Publications:

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

Correction to: N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ ATM pathway.

Following publication of the original article [1], the authors reported that name that appeared in published online version is incorrect. Aifeng Wang should be Aifen Wang. Corrected name is provided in the author group section above.
Authors
Yin, Y; Xu, L; Chang, Y; Zeng, T; Chen, X; Wang, A; Groth, J; Foo, W-C; Liang, C; Hu, H; Huang, J
MLA Citation
Yin, Yu, et al. “Correction to: N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ ATM pathway.Mol Cancer, vol. 18, no. 1, June 2019, p. 107. Pubmed, doi:10.1186/s12943-019-1034-y.
URI
https://scholars.duke.edu/individual/pub1393498
PMID
31217018
Source
pubmed
Published In
Molecular Cancer
Volume
18
Published Date
Start Page
107
DOI
10.1186/s12943-019-1034-y

N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway.

BACKGROUND: MYCN amplification or N-Myc overexpression is found in approximately 40% NEPC and up to 20% CRPC patients. N-Myc has been demonstrated to drive disease progression and hormonal therapeutic resistance of NEPC/CRPC. Here, we aim to identify the molecular mechanisms underlying the N-Myc-driven therapeutic resistance and provide new therapeutic targets for those N-Myc overexpressed NEPC/CRPC. METHODS: N-Myc overexpressing stable cell lines for LNCaP and C4-2 were generated by lentivirus infection. ADT-induced senescence was measured by SA-β-gal staining in LNCaP cells in vitro and in LNCaP xenograft tumors in vivo. Migration, cell proliferation and colony formation assays were used to measure the cellular response after overexpressing N-Myc or perturbing the miR-421/ATM pathway. CRISPR-Cas9 was used to knock out ATM in C4-2 cells and MTS cell viability assay was used to evaluate the drug sensitivity of N-Myc overexpressing C4-2 cells in response to Enzalutamide and ATM inhibitor Ku60019 respectively or in combination. RESULTS: N-Myc overexpression suppressed ATM expression through upregulating miR-421 in LNCaP cells. This suppression alleviated the ADT-induced senescence in vitro and in vivo. Surprisingly, N-Myc overexpression upregulated ATM expression in C4-2 cells and this upregulation promoted migration and invasion of prostate cancer cells. Further, the N-Myc-induced ATM upregulation in C4-2 cells rendered the cells resistance to Enzalutamide, and inhibition of ATM by CRISPR-Cas9 knockout or ATM inhibitor Ku60019 re-sensitized them to Enzalutamide. CONCLUSIONS: N-Myc differentially regulating miR-421/ATM pathway contributes to ADT resistance and Enzalutamide resistance development respectively. Combination treatment with ATM inhibitor re-sensitizes N-Myc overexpressed CRPC cells to Enzalutamide. Our findings would offer a potential combination therapeutic strategy using ATM kinase inhibitor and Enzalutamide for the treatment of a subset of mCRPC with N-Myc overexpression that accounts for up to 20% CRPC patients.
Authors
Yin, Y; Xu, L; Chang, Y; Zeng, T; Chen, X; Wang, A; Groth, J; Foo, W-C; Liang, C; Hu, H; Huang, J
MLA Citation
Yin, Yu, et al. “N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway.Mol Cancer, vol. 18, no. 1, Jan. 2019, p. 11. Pubmed, doi:10.1186/s12943-019-0941-2.
URI
https://scholars.duke.edu/individual/pub1365359
PMID
30657058
Source
pubmed
Published In
Molecular Cancer
Volume
18
Published Date
Start Page
11
DOI
10.1186/s12943-019-0941-2

ATM deficiency promotes progression of CRPC by enhancing Warburg effect.

ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration-resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here, we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism. We showed that ATM deficiency generated by CRISPR/Cas9 editing promoted CRPC cell proliferation and xenograft tumor growth. ATM deficiency altered cellular metabolism and enhanced Warburg effect in CRPC cells. We demonstrated that ATM deficiency shunted the glucose flux to aerobic glycolysis by upregulating LDHA expression, which generated more lactate and produced less mitochondrial ROS to promote CRPC cell growth. Inhibition of LDHA by siRNA or inhibitor FX11 generated less lactate and accumulated more ROS in ATM-deficient CRPC cells and therefore potentiated the cell death of ATM-deficient CRPC cells. These findings suggest a new therapeutic strategy for ATM-mutant CRPC patients by targeting LDHA-mediated glycolysis metabolism, which might be effective for the PARP inhibitor resistant mCRPC tumors.
Authors
Xu, L; Ma, E; Zeng, T; Zhao, R; Tao, Y; Chen, X; Groth, J; Liang, C; Hu, H; Huang, J
MLA Citation
Xu, Lingfan, et al. “ATM deficiency promotes progression of CRPC by enhancing Warburg effect.Endocr Relat Cancer, vol. 26, no. 1, Jan. 2019, pp. 59–71. Pubmed, doi:10.1530/ERC-18-0196.
URI
https://scholars.duke.edu/individual/pub1356922
PMID
30400006
Source
pubmed
Published In
Endocr Relat Cancer
Volume
26
Published Date
Start Page
59
End Page
71
DOI
10.1530/ERC-18-0196

Targeting androgen receptor-independent pathways in therapy-resistant prostate cancer.

Since androgen receptor (AR) signaling is critically required for the development of prostate cancer (PCa), targeting AR axis has been the standard treatment of choice for advanced and metastatic PCa. Unfortunately, although the tumor initially responds to the therapy, treatment resistance eventually develops and the disease will progress. It is therefore imperative to identify the mechanisms of therapeutic resistance and novel molecular targets that are independent of AR signaling. Recent advances in pathology, molecular biology, genetics and genomics research have revealed novel AR-independent pathways that contribute to PCa carcinogenesis and progression. They include neuroendocrine differentiation, cell metabolism, DNA damage repair pathways and immune-mediated mechanisms. The development of novel agents targeting the non-AR mechanisms holds great promise to treat PCa that does not respond to AR-targeted therapies.
Authors
Xu, L; Chen, J; Liu, W; Liang, C; Hu, H; Huang, J
MLA Citation
Xu, Lingfan, et al. “Targeting androgen receptor-independent pathways in therapy-resistant prostate cancer.Asian J Urol, vol. 6, no. 1, Jan. 2019, pp. 91–98. Pubmed, doi:10.1016/j.ajur.2018.11.002.
URI
https://scholars.duke.edu/individual/pub1370055
PMID
30775252
Source
pubmed
Published In
Asian Journal of Urology
Volume
6
Published Date
Start Page
91
End Page
98
DOI
10.1016/j.ajur.2018.11.002