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

Abstract

Summary 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 TACSTD2 high human prostate luminal epithelia cells highly express SOX2 and are relatively enriched in the transition zone prostate. Both TACSTD2 high and TACSTD2 low luminal cells transduced by activated AKT 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 TACSTD2 high 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 caAKT and c-Myc and reveals an impact of cellular status on initiation of lineage plasticity.

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

“…This hypothesis is supported by a recent study showing that high expression of TACSTD2 was associated with biochemical recurrence ( 26 ). In addition, our recent study demonstrated directly that, when transduced with activated AKT1 and c-Myc, the TACSTD2 high human prostate luminal cells possess a higher potential to undergo lineage plasticity and generate organoids containing distinct clinically relevant prostate tumor cell populations than the TACSTD2 low luminal cells ( 27 ). Prostate ductal adenocarcinoma (PDA) is rare but is the second common histological variant of prostatic carcinoma ( 28 , 29 ).…”

Novel insights in cell cycle dysregulation during prostate cancer progression

“…RB, loss), which impact their function, during CaP progression. Other important modulators of CaP cell proliferation that may be less readily recognized as cell cycle regulators include, for instance, PLK1, whose overexpression has been linked to prostate tumorigenesis (Weichert et al 2004, Deeraksa et al 2013, or MYC, whose gene amplification drives CaP/NEPC progression (Ellwood-Yen et al 2003, Kwon et al 2020. The full scope of CaP cell cycle modulators and the extent to which somatic alterations impact their expression or function, and subsequently, clinical CaP progression and treatment response, has likely not yet been determined.…”

Loss and revival of androgen receptor signaling in advanced prostate cancer

“…In this model, further differentiation to NEPC is critically dependent on p53 and RB1 loss [ 48 ]. Recently, Kwon et al showed that MYC’s overexpression, together with a constitutively activated AKT (caAKT), can drive lineage plasticity in human luminal cells–derived organoid [ 64 ]. As a plasticity consequence, MYC- and caAKT-overexpressed organoid showed heterogeneous expression of AR and neuroendocrine markers [ 64 ].…”

“…Recently, Kwon et al showed that MYC’s overexpression, together with a constitutively activated AKT (caAKT), can drive lineage plasticity in human luminal cells–derived organoid [ 64 ]. As a plasticity consequence, MYC- and caAKT-overexpressed organoid showed heterogeneous expression of AR and neuroendocrine markers [ 64 ]. Nevertheless, it remains to be determined if the de-differentiation can also occur in the absence of MYC.…”