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:

Role and targeting of PRMT5 in prostate cancer

Administered By
Pathology
Awarded By
Purdue University
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

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

Assaying Radiosensitivity of Ataxia-Telangiectasia.

Ataxia-Telangiectasia (A-T) is a prototypical genomic instability disorder with multi-organ deficiency and it is caused by the defective function of a single gene, ATM (Ataxia-Telangiectasia Mutated). Radiosensitivity, among the pleiotropic symptoms of A-T, reflects the basic physiological functions of ATM protein in the double strand break (DSB)-induced DNA damage response (DDR) and also restrains A-T patients from the conventional radiation therapy for their lymphoid malignancy. In this chapter, we describe two methods that have been developed in our lab to assess the radiosensitivity of A-T patients: (1) Colony Survival Assay (CSA) and (2) Flow Cytometry of phospho-SMC1 (FC-pSMC1). The establishment of these more rapid and reliable functional assays to measure the radiosensitivity, exemplified by A-T, would facilitate the diagnosis of other genomic instability genetic disorders as well as help the treatment options for most radiosensitive patients.
Authors
Hu, H; Nahas, S; Gatti, RA
MLA Citation
Hu, Hailiang, et al. “Assaying Radiosensitivity of Ataxia-Telangiectasia.Methods Mol Biol, vol. 1599, 2017, pp. 1–11. Pubmed, doi:10.1007/978-1-4939-6955-5_1.
URI
https://scholars.duke.edu/individual/pub1252836
PMID
28477107
Source
pubmed
Published In
Methods Mol Biol
Volume
1599
Published Date
Start Page
1
End Page
11
DOI
10.1007/978-1-4939-6955-5_1

MYC-induced reprogramming of glutamine catabolism supports optimal virus replication

Authors
Thai, M; Thaker, SK; Feng, J; Du, Y; Hu, H; Ting Wu, T; Graeber, TG; Braas, D; Christofk, HR
MLA Citation
Thai, Minh, et al. “MYC-induced reprogramming of glutamine catabolism supports optimal virus replication.” Nature Communications, vol. 6, no. 1, Springer Science and Business Media LLC, Dec. 2015. Crossref, doi:10.1038/ncomms9873.
URI
https://scholars.duke.edu/individual/pub1345124
Source
crossref
Published In
Nature Communications
Volume
6
Published Date
DOI
10.1038/ncomms9873