Elimination of SOX2/OCT4-Associated Prostate Cancer Stem Cells Blocks Tumor Development and Enhances Therapeutic Response

Prasanna Kumar Vaddi; Mark A Stamnes; Huojun Cao; Songhai Chen

doi:10.3390/cancers11091331

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Elimination of SOX2/OCT4-Associated Prostate Cancer Stem Cells Blocks Tumor Development and Enhances Therapeutic Response

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Elimination of SOX2/OCT4-Associated Prostate Cancer Stem Cells Blocks Tumor Development and Enhances Therapeutic Response

Prasanna Kumar Vaddi, Mark A Stamnes, Huojun Cao and Songhai Chen

Cancers, Vol.11(9), p.1331

09/01/2019

DOI: 10.3390/cancers11091331

PMCID: PMC6769476

PMID: 31500347

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Abstract

SOX2 and OCT4 are key regulators of embryonic stem cell pluripotency. They are overexpressed in prostate cancers and have been associated with cancer stem cell (CSC) properties. However, reliable tools for detecting and targeting SOX2/OCT4-overexpressing cells are lacking, limiting our understanding of their roles in prostate cancer initiation, progression, and therapeutic resistance. Here, we show that a fluorescent reporter called SORE6 can identify SOX2/OCT4-overexpressing prostate cancer cells. Among tumor cells, the SORE6 reporter identified a small fraction with CSC hallmarks: rapid self-renewal, the capability to form tumors and metastasize, and resistance to chemotherapies. Transcriptome and biochemical analyses identified PI3K/AKT signaling as critical for maintaining the SORE6 + population. Moreover, a SORE6-driven herpes simplex virus thymidine kinase (TK) expression construct could selectively ablate SORE6 + cells in tumors, blocking tumor initiation and progression, and sensitizing tumors to chemotherapy. This study demonstrates a key role of SOX2/OCT4-associated prostate cancer stem cells in tumor development and therapeutic resistance, and identifies the SORE6 reporter system as a useful tool for characterizing CSCs functions in a native tumor microenvironment.

SORE6 reporter

SOX2

OCT4

prostate cancer

cancer stem cells

suicide gene

Details

Title: Subtitle: Elimination of SOX2/OCT4-Associated Prostate Cancer Stem Cells Blocks Tumor Development and Enhances Therapeutic Response
Creators: Prasanna Kumar Vaddi - The Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Mark A Stamnes - The Department of Molecular Physiology and Physics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Huojun Cao - The Department of Endodontics, College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA 52242, USA
Songhai Chen - The Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Cancers, Vol.11(9), p.1331
DOI: 10.3390/cancers11091331
PMID: 31500347
PMCID: PMC6769476
NLM abbreviation: Cancers (Basel)
ISSN: 2072-6694
eISSN: 2072-6694
Publisher: MDPI
Grant note: DOI: 10.13039/100014039, name: DOD Prostate Cancer Research Program, award: PC111628; DOI: 10.13039/100000009, name: National Institutes of Health, award: R01CA207889
Language: English
Date published: 09/01/2019
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology; Endodontics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Dental Research; Internal Medicine
Record Identifier: 9984070144302771

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