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Prostate cancer (PC) is initially dependent on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with anti-tumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks (DSBs), G0/G1 cell cycle arrest and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA which was augmented by PARP1 inhibition. SPA-induced DSBs were accentuated in BRCA2-deficient PCs, and combining SPA with PARP or DNA-PKcs inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from PC patients receiving SPA as part of ongoing Phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to PCs with AR amplification or DNA repair deficiency, and for combining SPA therapy with PARP inhibition.

BMI1, a polycomb group (PcG) protein, plays a critical role in epigenetic regulation of cell differentiation and proliferation, and cancer stem cell self-renewal. BMI1 is upregulated in multiple types of cancer, including prostate cancer. As a key component of polycomb repressive complex 1 (PRC1), BMI1 exerts its oncogenic functions by enhancing the enzymatic activities of RING1B to ubiquitinate histone H2A at lysine 119 and repress gene transcription. Here, we report a PRC1-independent role of BMI1 that is critical for castration-resistant prostate cancer (CRPC) progression. BMI1 binds the androgen receptor (AR) and prevents MDM2-mediated AR protein degradation, resulting in sustained AR signaling in prostate cancer cells. More importantly, we demonstrate that targeting BMI1 effectively inhibits tumor growth of xenografts that have developed resistance to surgical castration and enzalutamide treatment. These results suggest that blocking BMI1 alone or in combination with anti-AR therapy can be more efficient to suppress prostate tumor growth. The polycomb group protein BMI1 is highly expressed in prostate cancer. Here, the authors demonstrate that BMI1 directly interacts with AR leading to increased AR signaling independently of PRC1 complex and that targeting BMI1 inhibits tumor growth of castration-resistant prostate cancer tumors.

Most patients with muscle‐invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up‐regulation of nuclear factor kappa light‐chain enhancer of activated B cells (NF‐κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF‐κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF‐κB signaling and patient survival. The efficacy of cisplatin plus the NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum‐naive claudin‐low MIBC showed constitutive NF‐κB signaling and this was associated with reduced disease‐specific survival in TCGA patients. Chemotherapy up‐regulated NF‐κB signaling and chemoresistance‐associated genes, including SPHK1, PLAUR, and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function, and morphology, reduced muscle fatigue and IL‐6 serum levels, and did not aggravate immuno‐hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF‐κB inhibition with platinum‐based chemotherapy and conducting a clinical trial in MIBC patients. NF‐κB up‐regulation promotes chemoresistance of muscle‐invasive bladder cancer (MIBC). The authors showed up‐regulated NF‐κB signaling in therapy‐naive MIBC subsets and post‐chemotherapy MIBC. Combining the NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) with cisplatin therapy increased antitumor efficacy, and prevented cachexia and nephrotoxicity compared with cisplatin alone, without aggravating immuno‐hematological parameters. These data support the combination of NF‐κB inhibition with platinum‐based chemotherapy for MIBC treatment.

Bladder cancer is among the most prevalent cancers worldwide. Currently, few bladder cancer models have undergone thorough characterization to assess their fidelity to patient tumors, especially upon propagation in the laboratory. Here, we establish and molecularly characterize CoCaB 1, an aggressive cisplatin-resistant muscle-invasive bladder cancer patient-derived xenograft (PDX) and companion organoid system. CoCaB 1 was a subcutaneous PDX model reliably transplanted in vivo and demonstrated an acceleration in growth upon serial transplantation, which was reflected in organoid and 2D cell culture systems. Transcriptome analysis revealed progression towards an increasingly proliferative and stem-like expression profile. Gene expression differences between organoid and PDX models reflected expected differences in cellular composition, with organoids enriched in lipid biosynthesis and metabolism genes and deprived of extracellular components observed in PDXs. Both PDX and organoid models maintained the histological fidelity and mutational heterogeneity of their parental tumor. This study establishes the CoCaB 1 PDX and organoid system as companion representative tumor models for the development of novel bladder cancer therapies.

Dissemination of prostate cancer (PCa) cells to the bone marrow is an early event in the disease process. In some patients, disseminated tumor cells (DTC) proliferate to form active metastases after a prolonged period of undetectable disease known as tumor dormancy. Identifying mechanisms of PCa dormancy and reactivation remain a challenge partly due to the lack of in vitro models. Here, we characterized in vitro PCa dormancy-reactivation by inducing cells from three patient-derived xenograft (PDX) lines to proliferate through tumor cell contact with each other and with bone marrow stroma. Proliferating PCa cells demonstrated tumor cell-cell contact and integrin clustering by immunofluorescence. Global gene expression analyses on proliferating cells cultured on bone marrow stroma revealed a downregulation of TGFB2 in all of the three proliferating PCa PDX lines when compared to their non-proliferating counterparts. Furthermore, constitutive activation of myosin light chain kinase (MLCK), a downstream effector of integrin-beta1 and TGF-beta2, in non-proliferating cells promoted cell proliferation. This cell proliferation was associated with an upregulation of CDK6 and a downregulation of E2F4. Taken together, our data provide the first clinically relevant in vitro model to support cellular adhesion and downregulation of TGFB2 as a potential mechanism by which PCa cells may escape from dormancy. Targeting the TGF-beta2-associated mechanism could provide novel opportunities to prevent lethal PCa metastasis.

Using genetically engineered mouse models, this work demonstrates that protein synthesis is essential for efficient urothelial cancer formation and growth but dispensable for bladder homeostasis. Through a candidate gene analysis for translation regulators implicated in this dependency, we discovered that phosphorylation of the translation initiation factor eIF4E at serine 209 is increased in both murine and human bladder cancer, and this phosphorylation corresponds with an increase in de novo protein synthesis. Employing an eIF4E serine 209 to alanine knock-in mutant mouse model, we show that this single posttranslational modification is critical for bladder cancer initiation and progression, despite having no impact on normal bladder tissue maintenance. Using murine and human models of advanced bladder cancer, we demonstrate that only tumors with high levels of eIF4E phosphorylation are therapeutically vulnerable to eFT508, the first clinical-grade inhibitor of MNK1 and MNK2, the upstream kinases of eIF4E. Our results show that phospho-eIF4E plays an important role in bladder cancer pathogenesis, and targeting its upstream kinases could be an effective therapeutic option for bladder cancer patients with high levels of eIF4E phosphorylation.

Bladder cancer is a prevalent but currently understudied cancer type and patient outcomes are poor when it progresses to the muscle-invasive stage. Current research in bladder cancer focuses on the genetic and epigenetic alterations occurring within the urothelial cell compartment; however, the stromal compartment receives less attention. Dynamic changes and intercellular communications occur in the tumour microenvironment (TME) of the bladder — a new concept and niche that we designate as the bladder TME (bTME) — during tumour evolution, metastatic progression and in the context of therapeutic response. Collagens and their cognate receptors, the discoidin domain receptors, have a role in various steps of the metastatic cascade and in immune checkpoint resistance. Furthermore, the presence of another TME niche, the metastatic TME (met-TME), is a novel concept that could support divergent progression of metastatic colonization in different organs, resulting in distant metastases with distinct characteristics and genetics from the primary tumour. The stroma has divergent roles in mediating therapeutic response to BCG immunotherapy and immune checkpoint inhibitors, as well as conventional chemotherapy or trimodality therapy (that is, maximal transurethral resection of bladder tumour, chemotherapy and radiotherapy). The local bTME and distant met-TME are currently conceptually and therapeutically unexploited niches that should be actively investigated. New biological insights from these TMEs will enable rational design of strategies that co-target the tumour and stroma, which are expected to improve the outcomes of patients with advanced bladder cancer.In this Review, the authors summarize current advances in our understanding of the roles of stroma and associated extracellular matrix during bladder cancer development, describing the bladder tumour microenvironment and introducing the concept of the metastatic tumour microenvironment.

TGFβ is a known driver of epithelial-mesenchymal transition (EMT) which is associated with tumor aggressiveness and metastasis. However, EMT has not been fully explored in clinical specimens of castration-resistant prostate cancer (CRPC) metastases. To assess EMT in CRPC, gene expression analysis was performed on 149 visceral and bone metastases from 62 CRPC patients and immunohistochemical analysis was performed on 185 CRPC bone and visceral metastases from 42 CRPC patients. In addition, to assess the potential of metastases to seed further metastases the mitochondrial genome was sequenced at different metastatic sites in one patient. TGFβ was increased in bone versus visceral metastases. While primarily cytoplasmic; nuclear and cytoplasmic Twist were significantly higher in bone than in visceral metastases. Slug and Zeb1 were unchanged, with the exception of nuclear Zeb1 being significantly higher in visceral metastases. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype. Underscoring the relevance of EMT-like cells, mitochondrial sequencing revealed that metastases could seed additional metastases in the same patient. In conclusion, while TGFβ expression and EMT-associated protein expression is present in a considerable number of CRPC visceral and bone metastases, nuclear Twist, Slug, and Zeb1 localization and an EMT-like phenotype (elongated nuclei and cytoplasmic compartment) was only present in a small subset of CRPC bone metastases. Mitochondrial sequencing from different metastases in a CRPC patient provided evidence for the seeding of metastases from previously established metastases, highlighting the biological relevance of EMT-like behavior in CRPC metastases.

Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental head and neck squamous cell carcinoma (HNSCC) dormancy models and in DTCs from prostate cancer patients carrying dormant disease for 7–18 years. NR2F1-dependent dormancy is recapitulated by a co-treatment with the DNA-demethylating agent 5-Aza-C and retinoic acid across various cancer types. NR2F1-induced quiescence is dependent on SOX9, RARβ and CDK inhibitors. Intriguingly, NR2F1 induces global chromatin repression and the pluripotency gene NANOG, which contributes to dormancy of DTCs in the bone marrow. When NR2F1 is blocked in vivo , growth arrest or survival of dormant DTCs is interrupted in different organs. We conclude that NR2F1 is a critical node in dormancy induction and maintenance by integrating epigenetic programmes of quiescence and survival in DTCs. Tumour cells disseminated from the primary tumour can remain dormant for years before initiating metastases. Here Sosa et al. show that the orphan nuclear receptor NR2F1 can be induced by bone marrow cues and by epigenetic drugs to promote quiescence and tumour cell dormancy in several cancer types.

Available genetically defined cancer models are limited in genotypic and phenotypic complexity and underrepresent the heterogeneity of human cancer. Here, we describe a combinatorial genetic strategy applied to an organoid transformation assay to rapidly generate diverse, clinically relevant bladder and prostate cancer models. Importantly, the clonal architecture of the resultant tumors can be resolved using single-cell or spatially resolved next-generation sequencing to uncover polygenic drivers of cancer phenotypes. An approach combining infection of primary human epithelial cells with a barcoded lentiviral-based library followed by engraftment into mice yields biologically relevant models of bladder and prostate cancer harboring complex genetic perturbations.