TY - JOUR
T1 - Novel, non-invasive markers for detecting therapy induced neuroendocrine differentiation in castration-resistant prostate cancer patients
AU - Bhagirath, Divya
AU - Liston, Michael
AU - Akoto, Theresa
AU - Lui, Byron
AU - Bensing, Barbara A.
AU - Sharma, Ashok
AU - Saini, Sharanjot
N1 - Funding Information:
We sincerely thank Dr. Felix Feng at UCSF for LNCaP-AR and LNCaP-AR-enzalutamide resistant cell line and Dr. Santu Ghosh, at Augusta University for his help with data analyses. This work is supported by the US Army Medical Research Acquisition Activity (USAMRAA) through the Idea Development Award under Award No. W81XWH-18-1-0303 and W81XWH-18-2-0013. Additionally, supported by Award no. W81XWH-18-2-0015, W81XWH-18-2-0016, W81XWH-18-2-0017, W81XWH-18-2-0018, and W81XWH-18-2-0019 PCa Bioreposi-tory Network (PCBN). Funding support by the National Cancer Institute at the National Institutes of Health (Grant Number RO1CA177984) is also acknowledged. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense or U.S. Army.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Neuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.
AB - Neuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.
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U2 - 10.1038/s41598-021-87441-2
DO - 10.1038/s41598-021-87441-2
M3 - Article
C2 - 33859239
AN - SCOPUS:85104386598
SN - 2045-2322
VL - 11
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 8279
ER -
