@article{a5b352870a9e45b29da34085b1c466c9,
title = "Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1",
abstract = "Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2- driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.",
keywords = "Cancer, NEPC, Prostate, Trop2",
author = "Hsu, {En Chi} and Rice, {Meghan A.} and Abel Bermudez and Marques, {Fernando Jose Garcia} and Merve Aslan and Shiqin Liu and Ali Ghoochani and Zhang, {Chiyuan Amy} and Chen, {Yun Sheng} and Aimen Zlitni and Sahil Kumar and Rosalie Nolley and Frezghi Habte and Michelle Shen and Kashyap Koul and Peehl, {Donna M.} and Amina Zoubeidi and Gambhir, {Sanjiv S.} and Kunder, {Christian A.} and Pitteri, {Sharon J.} and Brooks, {James D.} and Tanya Stoyanova",
note = "Funding Information: ACKNOWLEDGMENTS. This work was supported by the Canary Foundation; by NIH/National Cancer Institute K99/R00 Award 4R00CA184397 (to T.S.), R03CA230819 (to T.S.), and U01 CA196387 (to J.D.B.); by Department of Defense Congressionally Directed Medical Research Program (CDMRP) Grants W81XWH1810323 (to T.S.) and W81XWH1810141 (to M.A.R.); and by NIH under Award S10 OD023518-01A1 for the Celigo S Imaging Cytometer (200-BFFL-S). Opinions, interpretation, conclusions, and recommendations are those of the authors and not necessarily endorsed by the US Army. Funding Information: 23. M. K. Bakht et al., Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. Endocr. Relat. Cancer 26, 131–146 (2018). Methods Detailed methods are available in SI Appendix, SI Methods. Lentiviral Production and Concentration. Lentiviral plasmids FUCRW, FUCRW-Trop2-Flag, pLKO.1-control scramble short hairpin RNA (shRNA) vector, or pLKO.1-Trop2 shRNA were cotransfected using third generation packaging systems, including pMDLg/pRRE, pRSV-Rev, and pMD2.G, into 293T cells using standard calcium phosphate transfection. The media with viral particles were collected for 2 d, filtered using a 0.45-μm filter, and concentrated using ultracentrifugation (25,000 rpm, 2 h). The viral titer was determined through serial dilution of concentrated viruses and infection of 2 × 105 293T cells in six-well plates. The percentage of infected cells (viral titer) was analyzed by the Guava easyCyte Flow Cytometer (EMD Millipore) based on GFP or RFP expression 72 h postinfection. Human Tissues (Tissue Microarrays). All human samples were deidentified prior to use in this study. Data Availability Statement. All data and associated protocols are included in the manuscript and available to the readers. 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year = "2020",
month = jan,
day = "28",
doi = "10.1073/pnas.1905384117",
language = "English (US)",
volume = "117",
pages = "2032--2042",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "4",
}