학술논문
Activation of neural lineage networks and ARHGEF2 in enzalutamide-resistant and neuroendocrine prostate cancer and association with patient outcomes
Document Type
Original Paper
Author
Source
Communications Medicine. 2(1)
Subject
Language
English
ISSN
2730-664X
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.
Plain language summary: Neuroendocrine prostate cancer is an aggressive subtype of prostate cancer that can arise in patients after treatment with drugs that suppress androgen hormone activity. Treatment options are limited for neuroendocrine prostate cancer and survival is poor, so it is important to identify markers to identify this subtype and how it relates to patient outcome. We use cells and patient datasets to identify a signature of 95 genes that can distinguish neuroendocrine prostate cancer from the more common prostate adenocarcinoma. Levels of a subset of these genes are associated with shortened survival time in patients. We show that one of these genes, ARHGEF2, helps to maintain survival and neuroendocrine features in prostate cancer cells. Our findings could help clinicians to identify patients with neuroendocrine prostate cancer and predict outcome in these patients, and help researchers to identify potential drug targets.
Ning et al. report expression of a neural lineage gene signature in enzalutamide-resistant prostate cancer cells and datasets from patients with neuroendocrine prostate cancer. One of these genes, ARHGEF2, is associated with poor overall and disease-free survival in patients with castration-resistant disease and supports cell viability in vitro.
Plain language summary: Neuroendocrine prostate cancer is an aggressive subtype of prostate cancer that can arise in patients after treatment with drugs that suppress androgen hormone activity. Treatment options are limited for neuroendocrine prostate cancer and survival is poor, so it is important to identify markers to identify this subtype and how it relates to patient outcome. We use cells and patient datasets to identify a signature of 95 genes that can distinguish neuroendocrine prostate cancer from the more common prostate adenocarcinoma. Levels of a subset of these genes are associated with shortened survival time in patients. We show that one of these genes, ARHGEF2, helps to maintain survival and neuroendocrine features in prostate cancer cells. Our findings could help clinicians to identify patients with neuroendocrine prostate cancer and predict outcome in these patients, and help researchers to identify potential drug targets.
Ning et al. report expression of a neural lineage gene signature in enzalutamide-resistant prostate cancer cells and datasets from patients with neuroendocrine prostate cancer. One of these genes, ARHGEF2, is associated with poor overall and disease-free survival in patients with castration-resistant disease and supports cell viability in vitro.