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.
Highlights
Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer deaths in American men [1]
Through the transcriptome profiling of SORE6+ cells, we identified PI3K/AKT signaling as the pathway key to maintaining the prostate SOX2/OCT4-overexpressing cancer stem cell (CSC) population
SOX2/OCT4-overexpressing prostate cancer cells with CSC characteristics. Based on this system, we developed a valuable tool for the selective elimination of SOX2/OCT4-overexpressing
Summary
Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer deaths in American men [1]. The progression of localized PCa to metastatic disease significantly shortens patient survival, because of the development of resistance to contemporary treatments, including the combination of castration and taxane chemotherapy [1]. One mechanism proposed to explain how PCa can progress to castration and chemotherapy resistance argues that, within a tumor, increasingly aggressive cells arise from a small population of stem-like cells—called tumor-initiating cells/cancer stem cells (CSCs) [2]. CSCs were initially discovered in acute myelogenous leukemia and later found in many types of solid tumors, including prostate cancer [3,4]. CSCs comprise the top of the tumor cell hierarchy. They are a class of pluripotent cells that
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