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Background Prostate cancer (PCa) is the most common malignant neoplasm among men in many countries. Since most precancerous and cancerous tissues show signs of inflammation, chronic bacterial prostatitis has been hypothesized to be a possible etiology. However, establishing a causal relationship between microbial inflammation and PCa requires a comprehensive analysis of the prostate microbiome. The aim of this study was to characterize the microbiome in prostate tissue of PCa patients and investigate its association with tumour clinical characteristics as well as host expression profiles. Results The metagenome and metatranscriptome of tumour and the adjacent benign tissues were assessed in 65 Chinese radical prostatectomy specimens. Escherichia , Propionibacterium , Acinetobacter and Pseudomonas were abundant in both metagenome and metatranscriptome, thus constituting the core of the prostate microbiome. The biodiversity of the microbiomes could not be differentiated between the matched tumour/benign specimens or between the tumour specimens of low and high Gleason Scores. The expression profile of ten Pseudomonas genes was strongly correlated with that of eight host small RNA genes; three of the RNA genes may negatively associate with metastasis. Few viruses could be identified from the prostate microbiomes. Conclusions This is the first study of the human prostate microbiome employing an integrated metagenomics and metatranscriptomics approach. In this Chinese cohort, both metagenome and metatranscriptome analyses showed a non-sterile microenvironment in the prostate of PCa patients, but we did not find links between the microbiome and local progression of PCa. However, the correlated expression of Pseudomonas genes and human small RNA genes may provide tantalizing preliminary evidence that Pseudomonas infection may impede metastasis.

Background Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. Methods To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. Results We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1 . To further investigate the role of BAP1 , we used our recently developed cancer driver gene prioritization algorithm, HIT’nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. Conclusions Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.

Prostate cancer (PCa) is driven by the androgen receptor (AR)‐signaling axis. Hormonal therapy often mitigates PCa progression, but a notable number of cases progress to castration‐resistant PCa (CRPC). CRPC retains AR activity and is incurable. Long noncoding RNA (lncRNA) represent an uncharted region of the transcriptome. Several lncRNA have been recently described to mediate oncogenic functions, suggesting that these molecules can be potential therapeutic targets. Here, we identified CRPC‐associated lncRNA by analyzing patient‐derived xenografts (PDXs) and clinical data. Subsequently, we characterized one of the CRPC‐promoting lncRNA, HORAS5, in vitro and in vivo. We demonstrated that HORAS5 is a stable, cytoplasmic lncRNA that promotes CRPC proliferation and survival by maintaining AR activity under androgen‐depleted conditions. Most strikingly, knockdown of HORAS5 causes a significant reduction in the expression of AR itself and oncogenic AR targets such as KIAA0101. Elevated expression of HORAS5 is also associated with worse clinical outcomes in patients. Our results from HORAS5 inhibition in in vivo models further confirm that HORAS5 is a viable therapeutic target for CRPC. Thus, we posit that HORAS5 is a novel, targetable mediator of CRPC through its essential role in the maintenance of oncogenic AR activity. Overall, this study adds to our mechanistic understanding of how lncRNA function in cancer progression. Long non‐coding RNA (lncRNA) are novel players in cancer progression. Here, we identified a lncRNA, HORAS5, which is upregulated in castration‐resistant prostate cancer (CRPC) and is associated with worse clinical outcomes. HORAS5 promotes CRPC survival by increasing AR mRNA stability, thereby augmenting the androgen receptor transcriptional program. Knockdown of HORAS5 in vitro and in vivo attenuates proliferation and induces cell apoptosis.

The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC‐associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient‐derived, treatment‐related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC. In this study, we report the establishment of a novel patient‐derived xenograft model of t‐NEPC and the successful establishment of the KUCaP13 cell line. The cell line can be maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering. The cell line should be a valuable tool for research to identify novel therapeutic targets of NEPC and to develop effective therapeutic agents.

TEAD4 (TEA Domain Transcription Factor 4) is well recognized as the DNA-anchor protein of YAP transcription complex, which is modulated by Hippo, a highly conserved pathway in Metazoa that controls organ size through regulating cell proliferation and apoptosis. To acquire full transcriptional activity, TEAD4 requires co-activator, YAP (Yes-associated protein) or its homolog TAZ (transcriptional coactivator with PDZ-binding motif) the signaling hub that relays the extracellular stimuli to the transcription of target genes. Growing evidence suggests that TEAD4 also exerts its function in a YAP-independent manner through other signal pathways. Although TEAD4 plays an essential role in determining that differentiation fate of the blastocyst, it also promotes tumorigenesis by enhancing metastasis, cancer stemness, and drug resistance. Upregulation of TEAD4 has been reported in several cancers, including colon cancer, gastric cancer, breast cancer, and prostate cancer and serves as a valuable prognostic marker. Recent studies show that TEAD4, but not other members of the TEAD family, engages in regulating mitochondrial dynamics and cell metabolism by modulating the expression of mitochondrial- and nuclear-encoded electron transport chain genes. TEAD4’s functions including oncogenic activities are tightly controlled by its subcellular localization. As a predominantly nuclear protein, its cytoplasmic translocation is triggered by several signals, such as osmotic stress, cell confluency, and arginine availability. Intriguingly, TEAD4 is also localized in mitochondria, although the translocation mechanism remains unclear. In this report, we describe the current understanding of TEAD4 as an oncogene, epigenetic regulator and mitochondrial modulator. The contributing mechanisms will be discussed.

Background Although low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective. Recognizing that these cancers may be driven by MAPK pathway activation, MEK inhibitors (MEKi) are being tested in clinical trials. LGSC respond to MEKi only in a subgroup of patients, so predictive biomarkers and better therapies will be needed. Methods We evaluated a number of patient-derived LGSC cell lines, previously classified according to their MEKi sensitivity. Two cell lines were genomically compared against their matching tumors samples. MEKi-sensitive and MEKi-resistant lines were compared using whole exome sequencing and reverse phase protein array. Two treatment combinations targeting MEKi resistance markers were also evaluated using cell proliferation, cell viability, cell signaling, and drug synergism assays. Results Low-grade serous ovarian cancer cell lines recapitulated the genomic aberrations from their matching tumor samples. We identified three potential predictive biomarkers that distinguish MEKi sensitive and resistant lines: KRAS mutation status, and EGFR and PKC-alpha protein expression. The biomarkers were validated in three newly developed LGSC cell lines. Sub-lethal combination of MEK and EGFR inhibition showed drug synergy and caused complete cell death in two of four MEKi-resistant cell lines tested. Conclusions KRAS mutations and the protein expression of EGFR and PKC-alpha should be evaluated as predictive biomarkers in patients with LGSC treated with MEKi. Combination therapy using a MEKi with EGFR inhibition may represent a promising new therapy for patients with MEKi-resistant LGSC.

Development of neuroendocrine prostate cancer (NEPC) is emerging as a major problem in clinical management of advanced prostate cancer (PCa). As increasingly potent androgen receptor (AR)‐targeting antiandrogens are more widely used, PCa transdifferentiation into AR‐independent NEPC as a mechanism of treatment resistance becomes more common and precarious, since NEPC is a lethal PCa subtype urgently requiring effective therapy. Reprogrammed glucose metabolism of cancers, that is elevated aerobic glycolysis involving increased lactic acid production/secretion, plays a key role in multiple cancer‐promoting processes and has been implicated in therapeutics development. Here, we examined NEPC glucose metabolism using our unique panel of patient‐derived xenograft PCa models and patient tumors. By calculating metabolic pathway scores using gene expression data, we found that elevated glycolysis coupled to increased lactic acid production/secretion is an important metabolic feature of NEPC. Specific inhibition of expression of MCT4 (a plasma membrane lactic acid transporter) by antisense oligonucleotides led to reduced lactic acid secretion as well as reduced glucose metabolism and NEPC cell proliferation. Taken together, our results indicate that elevated glycolysis coupled to excessive MCT4‐mediated lactic acid secretion is clinically relevant and functionally important to NEPC. Inhibition of MCT4 expression appears to be a promising therapeutic strategy for NEPC. Neuroendocrine prostate cancer (NEPC) is considered a next‐generation clinical problem in prostate cancer management in urgent need of effective therapeutic strategies. This is the first description of NEPC metabolism in a clinically relevant and biologically functional manner, filling in a crucial knowledge gap regarding the metabolic phenotype of NEPC and its therapeutic possibilities.

Prostate cancer (PCa) stands as a leading cause of cancer‐related mortality among men, with treatment‐induced neuroendocrine prostate cancer (NEPC) posing a challenge as an ARPI‐resistant subtype. The role of transcription factors (TFs) in PCa progression and NEPC transdifferentiation remains inadequately understood, underscoring a critical gap in current research. In this study, an internal Z score‐based approach is developed to identify lineage‐specific TF profiles in prostatic adenocarcinoma and NEPC for a nuanced understanding of TF expression dynamics. Distinct TF profiles for adenocarcinoma and NEPC are unveiled, identifying 126 shared TFs, 46 adenocarcinoma‐TFs, and 56 NEPC‐TFs, validated across multiple cohorts. Gene Ontology is employed to validate their biological and functional roles in PCa progression. Implications are revealed in cell development, differentiation, and lineage determination. Knockdown experiments suggest that lineage‐TFs are functionally important in maintaining lineage‐specific cell proliferation. Additionally, a longitudinal study on NE transdifferentiation highlights dynamic TF expression shifts, proposing a three‐phases hypothesis for PCa progression mechanisms. This study introduces a groundbreaking approach for deciphering the TF landscape in PCa, providing a molecular basis for adenocarcinoma to NEPC progression, and paving the way for innovative treatment strategies with potential impact on patient outcomes. The study deciphers the landscapes of lineage‐related transcription factors in prostatic adenocarcinoma and neuroendocrine prostate cancer using an innovative approach. These findings, validated across cohorts, highlight TFs' roles in cell development and offer novel therapeutic targets. A longitudinal study on dynamic shift of lineage‐TFs reveals a “three‐phase hypothesis” for NE transdifferentiation, providing crucial insights into prostate cancer progression mechanisms.

Background Chromothripsis, a newly discovered type of complex genomic rearrangement, has been implicated in the evolution of several types of cancers. To date, it has been described in bone cancer, SHH-medulloblastoma and acute myeloid leukemia, amongst others, however there are still no formal or automated methods for detecting or annotating it in high throughput sequencing data. As such, findings of chromothripsis are difficult to compare and many cases likely escape detection altogether. Results We introduce ShatterProof, a software tool for detecting and quantifying chromothriptic events. ShatterProof takes structural variation calls (translocations, copy-number variations, short insertions and loss of heterozygosity) produced by any algorithm and using an operational definition of chromothripsis performs robust statistical tests to accurately predict the presence and location of chromothriptic events. Validation of our tool was conducted using clinical data sets including matched normal, prostate cancer samples in addition to the colorectal cancer and SCLC data sets used in the original description of chromothripsis. Conclusions ShatterProof is computationally efficient, having low memory requirements and near linear computation time. This allows it to become a standard component of sequencing analysis pipelines, enabling researchers to routinely and accurately assess samples for chromothripsis. Source code and documentation can be found at http://search.cpan.org/~sgovind/Shatterproof .

Background While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities. Results In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis. Conclusions Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.