De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that either develops de novo or arises from prostate adenocarcinoma as a result of treatment resistance. Although the prostate basal cells have been shown to directly generate tumor cells with neuroendocrine features when transduced with oncogenic signaling, the identity of the cell-of-origin for de novo NEPC remains unclear. We show that the TACSTD2high human prostate luminal epithelia cells highly express SOX2 and are relatively enriched in the transition zone prostate. Both TACSTD2high and TACSTD2low luminal cells transduced by constitutively activated AKT1 (caAKT1), and c-Myc can form organoids containing versatile clinically relevant tumor cell lineages with regard to the expression of AR and the neuroendocrine cell markers Synaptophysin and Chromogranin A. Tumor organoid cells derived from the TACSTD2high luminal cells are more predisposed to neuroendocrine differentiation along passaging and are relatively more castration-resistant. Knocking down TACSTD2 and SOX2 both attenuate neuroendocrine differentiation of tumor organoid cells. This study demonstrates de novo neuroendocrine differentiation of the human prostate luminal epithelial cells induced by caAKT1 and c-Myc and reveals an impact of cellular status on initiation of lineage plasticity.

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Fig. 1: TACSTD2high luminal cells highly express SOX2 and enriched in human prostate transition zone.
Fig. 2: Human prostate luminal cells overexpressing caAKT1 and c-MYC exhibit lineage plasticity in prostate organoid assay.
Fig. 3: TACSTD2high luminal cells are more predisposed to NE differentiation dependent of TACSTD2 and SOX2.
Fig. 4: Prostate tumor organoids from TACSTD2high luminal cells show androgen resistance.

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Funding

This work was supported by R01CA190378, R01DK092202, and R01DK107436 (L.X.).

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Conception and design: LX and OK. Development of methodology: LX and OK. Acquisition of data: OK, LZ, DJ, ZZ, and ZL. Analysis and interpretation of data: OK, LZ, DJ, MH, and LX. Writing, review, and/or revision of the manuscript: LX and OK. Administrative, technical, or material support: LZ, DJ, LT, CM, and JKL, Study supervision: LX.

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Correspondence to Li Xin.

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Kwon, OJ., Zhang, L., Jia, D. et al. De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc. Oncogene 39, 7142–7151 (2020). https://doi.org/10.1038/s41388-020-01487-6

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