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Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells

Oncogene volume 40, pages 203–214 (2021)Cite this article

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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.

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Fig. 1: Both Sca-1+ and Sca-1− luminal cells can serve as targets for transformation induced by Pten loss.
Fig. 2: Prostate cancer derived from Sca-1+ luminal cells displays castration resistance.
Fig. 3: Transplantation experiment corroborates that prostate cancer derived from Sca-1+ luminal cells displays castration resistance.
Fig. 4: Androgen deprivation drives neuroendocrine differentiation of prostate cancer cells at proximal ducts of K8-Pten mice.
Fig. 5: Sox2 is not essential for the castration-resistant property.
Fig. 6: Sox2 is necessary for androgen deprivation-induced neuroendocrine differentiation of Pten-null prostate tumor cells.

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Acknowledgements

This work is supported by R01CA190378 (LX).

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Authors and Affiliations

  1. Department of Urology, University of Washington, Seattle, WA, 98109, USA

    Oh-Joon Kwon, Li Zhang, Deyong Jia & Li Xin

  2. Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA

    Li Xin

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Contributions

Conception and design: LX and OK. Development of methodology: LX and OK. Acquisition of data: OK, LZ, and DJ. Analysis and interpretation of data: OK, LZ, DJ, and LX. Writing, review, and/or revision of the paper: LX and OK. Study supervision: LX.

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Correspondence to Li Xin.

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All the mice used in this study received humane care in compliance with the principles stated in the Guide for the Care and Use of Laboratory Animals, NIH Publication, 1996 edition, and the protocols were approved by the Institutional Animal Care Committee at the University of Washington.

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Kwon, OJ., Zhang, L., Jia, D. et al. Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells. Oncogene 40, 203–214 (2021). https://doi.org/10.1038/s41388-020-01526-2

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