Activation of neural lineage networks and ARHGEF2 in enzalutamide-resistant and neuroendocrine prostate cancer and association with patient outcomes

Shu Ning; Jinge Zhao; Alan P Lombard; Leandro S D'Abronzo; Amy R Leslie; Masuda Sharifi; Wei Lou; Chengfei Liu; Joy C Yang; Christopher P Evans; Eva Corey; Hong-Wu Chen; Aiming Yu; Paramita M Ghosh; Allen C Gao

doi:10.1038/s43856-022-00182-9

Activation of neural lineage networks and ARHGEF2 in enzalutamide-resistant and neuroendocrine prostate cancer and association with patient outcomes

Commun Med (Lond). 2022 Sep 21:2:118. doi: 10.1038/s43856-022-00182-9. eCollection 2022.

Authors

Shu Ning¹, Jinge Zhao^{1

2}, Alan P Lombard¹, Leandro S D'Abronzo¹, Amy R Leslie¹, Masuda Sharifi¹, Wei Lou¹, Chengfei Liu^{1

3}, Joy C Yang¹, Christopher P Evans^{1

3}, Eva Corey⁴, Hong-Wu Chen^{3

5}, Aiming Yu^{3

5}, Paramita M Ghosh^{1

3

5

6}, Allen C Gao^{1

3

6}

Affiliations

¹ Department of Urologic Surgery, University of California Davis, Sacramento, CA USA.
² Present Address: Department of Urology, West China Hospital, Sichuan University, Sichuan, China.
³ UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA USA.
⁴ Department of Urology, University of Washington, Seattle, WA USA.
⁵ Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA USA.
⁶ VA Northern California Health Care System, Sacramento, CA USA.

Abstract

Background: Treatment-emergent neuroendocrine prostate cancer (NEPC) after androgen receptor (AR) targeted therapies is an aggressive variant of prostate cancer with an unfavorable prognosis. The underlying mechanisms for early neuroendocrine differentiation are poorly defined and diagnostic and prognostic biomarkers are needed.

Methods: We performed transcriptomic analysis on the enzalutamide-resistant prostate cancer cell line C4-2B MDVR and NEPC patient databases to identify neural lineage signature (NLS) genes. Correlation of NLS genes with clinicopathologic features was determined. Cell viability was determined in C4-2B MDVR and H660 cells after knocking down ARHGEF2 using siRNA. Organoid viability of patient-derived xenografts was measured after knocking down ARHGEF2.

Results: We identify a 95-gene NLS representing the molecular landscape of neural precursor cell proliferation, embryonic stem cell pluripotency, and neural stem cell differentiation, which may indicate an early or intermediate stage of neuroendocrine differentiation. These NLS genes positively correlate with conventional neuroendocrine markers such as chromogranin and synaptophysin, and negatively correlate with AR and AR target genes in advanced prostate cancer. Differentially expressed NLS genes stratify small-cell NEPC from prostate adenocarcinoma, which are closely associated with clinicopathologic features such as Gleason Score and metastasis status. Higher ARGHEF2, LHX2, and EPHB2 levels among the 95 NLS genes correlate with a shortened survival time in NEPC patients. Furthermore, downregulation of ARHGEF2 gene expression suppresses cell viability and markers of neuroendocrine differentiation in enzalutamide-resistant and neuroendocrine cells.

Conclusions: The 95 neural lineage gene signatures capture an early molecular shift toward neuroendocrine differentiation, which could stratify advanced prostate cancer patients to optimize clinical treatment and serve as a source of potential therapeutic targets in advanced prostate cancer.

Keywords: Prostate; Prostate cancer.

Abstract

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