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Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal
Oh-Joon Kwon1, Li Zhang1, Deyong Jia1
1Department of Urology, University of Washington, Seattle, WA, 98109, USA.
Abstract:
Prostate adenocarcinoma undergoes neuroendocrine differentiation to acquire resistance toward antihormonal therapies. The underlying mechanisms have been investigated extensively, among which Sox2 has been shown to play a critical role. However, genetic evidence in mouse models for prostate cancer to support the crucial role of Sox2 is missing. The adult mouse prostate luminal cells contain both castration-resistant Sox2-expressing Sca-1+ cells and castration-responsive Sca-1- cells. We show that both types of the luminal cell are susceptible to oncogenic transformation induced by loss of function of the tumor suppressor Pten. The tumors derived from the Sca-1+ cells are castration resistant and are more inclined to develop castration-induced neuroendocrine differentiation. Genetic ablation of Sox2 suppresses neuroendocrine differentiation but does not impact the castration-resistant property. This study provides direct genetic evidence that Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation of Pten null prostate adenocarcinoma, corroborates that the lineage status of the prostate cancer cells is a determinant for its propensity to exhibit lineage plasticity, and supports that the intrinsic features of cell-of-origin for prostate cancers can dictate their clinical behaviors.
Insights
Sox2 is essential for neuroendocrine differentiation in prostate cancer, a process linked to treatment resistance. Genetic evidence in mouse models confirms Sox2
Area of Science:
- * Oncology
- * Molecular Biology
- * Urology
Background:
- * Prostate adenocarcinoma can develop resistance to antihormonal therapies via neuroendocrine differentiation.
- * Sox2 has been implicated in this process, but genetic evidence in mouse models was lacking.
- * Mouse prostate luminal cells include castration-resistant Sox2-expressing Sca-1+ and castration-responsive Sca-1- cells.
Purpose of the Study:
- * To investigate the role of Sox2 in prostate cancer neuroendocrine differentiation using genetic mouse models.
- * To determine if Sox2 is crucial for castration-induced neuroendocrine differentiation in Pten-null prostate adenocarcinoma.
- * To explore the influence of cell-of-origin and lineage status on prostate cancer plasticity.
Main Methods:
- * Creation of Pten-null prostate adenocarcinoma mouse models.
- * Genetic ablation of Sox2 in these models.
- * Analysis of castration resistance and neuroendocrine differentiation.
- * Characterization of Sox2-expressing Sca-1+ and Sca-1- luminal cells.
Main Results:
- * Both Sca-1+ and Sca-1- luminal cells are susceptible to oncogenic transformation upon Pten loss.
- * Tumors from Sca-1+ cells exhibit castration resistance and neuroendocrine differentiation.
- * Genetic ablation of Sox2 inhibits neuroendocrine differentiation but not castration resistance.
- * Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation in Pten-null prostate adenocarcinoma.
Conclusions:
- * Sox2 is genetically proven to be necessary for castration-induced neuroendocrine differentiation in prostate cancer.
- * The lineage status of prostate cancer cells influences their propensity for lineage plasticity.
- * Intrinsic cell-of-origin features dictate prostate cancer clinical behavior and treatment response.
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