Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.

Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc‐mutant disease phenotype. This mechanism appears to be different than that for ADPKD. The murine models described here closely resemble the human disease and both appear to be mTORC1 inhibitor responsive. The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.

Accumulating evidence suggests that regulation of RNA processing through an RNP-driven mechanism is important for coordinated gene expression. This hypothesis predicts that defects in RNP biogenesis will adversely affect the elaboration of specific gene expression programs. To explore the role of RNP biogenesis on mammalian development, we have characterized the phenotype of mice hypomorphic for Thoc1. Thoc1 encodes an essential component of the evolutionarily conserved TREX complex. TREX accompanies the elongating RNA polymerase II and facilitates RNP assembly and recruitment of RNA processing factors. Hypomorphic Thoc1 mice are viable despite significantly reduced Thoc1 expression in the tissues examined. While most tissues of Thoc1-deficient mice appear to develop and function normally, gametogenesis is severely compromised. Male infertility is associated with a loss in spermatocyte viability and abnormal endocrine signaling. We suggest that loss of spermatocyte viability is a consequence of defects in the expression of genes required for normal differentiation of cell types within the testes. A number of the genes affected appear to be direct targets for regulation by Thoc1. These findings support the notion that Thoc1-mediated RNP assembly contributes to the coordinated expression of genes necessary for normal differentiation and development in vivo.The coordinated expression of functionally related genes is required for normal cellular differentiation, development, homeostasis, and responses to environmental stimuli. The combinatorial action of sequence-specific DNA binding transcription factors at promoters provides the foundation for coordinated gene expression. However, even tissue-restricted gene expression is fraught with considerable stochastic noise (2, 28, 39). Furthermore, transcription may be coordinately initiated at genes that vary considerably in length, exon-intron structure, and primary nucleotide sequence. Thus, the speeds and efficiencies of transcriptional elongation, RNA processing, nuclear export, and protein translation may differ considerably from gene to gene. Accumulating evidence indicates that these postinitiation events may be regulated through a ribonucleoprotein particle (RNP)-driven mechanism (25). It has been suggested that dynamic RNP formation may segregate premRNAs into "RNA regulons" to ensure coordinated protein production from functionally related genes (13). Disruption of this regulation is predicted to compromise the elaboration of specific gene expression programs, some of which may affect cellular differentiation and development. In vivo evidence in support of this prediction is lacking, particularly in higher eukaryotes.The evolutionarily conserved TREX protein complex contributes to RNP biogenesis and RNA processing. The metazoan Thoc1 gene and its Saccharomyces cerevisiae functional orthologue HPR1 (both orthologues are subsequently referred to as Thoc1 for simplicity) encode proteins that are essential components of the TREX complex (35). Thoc1 protein (pThoc1) ...

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Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of human NEPrCa. Immunostaining analysis of SKO, DKO and TKO tumors shows that αVβ3 integrin expression is increased in DKO and TKO primary tumors and metastatic lesions, but absent in SKO primary tumors. On the other hand, SKO tumors show higher levels of a different αV integrin, αVβ6, as compared to DKO and TKO tumors. These results are confirmed by RNA-sequencing analysis. Moreover, TRAMP mice, which carry NEPrCa and adenocarcinoma of the prostate, also have increased levels of αVβ3 in their NEPrCa primary tumors. In contrast, the αVβ6 integrin is only detectable in the adenocarcinoma areas. Finally, analysis of 42 LuCaP patient-derived xenografts and primary adenocarcinoma samples shows a positive correlation between αVβ3, but not αVβ6, and the neuronal marker synaptophysin; it also demonstrates that αVβ3 is absent in prostatic adenocarcinomas. In summary, we demonstrate that αVβ3 integrin is upregulated in NEPrCa primary and metastatic lesions; in contrast, the αVβ6 integrin is confined to adenocarcinoma of the prostate. Our findings suggest that the αVβ3 integrin, but not αVβ6, may promote a shift in lineage plasticity towards a NE phenotype and might serve as an informative biomarker for the early detection of NE differentiation in prostate cancer.