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CONTEXT: Mutations in the speckle-type POZ (SPOP) gene are frequently identified in prostate cancer (PC); yet, prognostic implications for affected patients remain unclear. Limited consensus exists regarding tailored treatments for SPOP-mutant (SPOPmut) PC. OBJECTIVE: To elucidate the prognostic and predictive significance of SPOP mutations across distinct PC stages and treatments. EVIDENCE ACQUISITION: A systematic literature search of PubMed, Embase, and Scopus was conducted up to January 29, 2024. The meta-analysis included studies comparing survival outcomes between SPOPmut and SPOP wild-type (SPOPwt) PC. EVIDENCE SYNTHESIS: From 669 records, 26 studies (including five abstracts) were analyzed. A meta-analysis of metastasis-free survival in localized (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.59-0.88; p < 0.01) and overall survival (OS) in metastatic PC (HR: 0.64, 95% CI: 0.53-0.76; p < 0.01) showed a favorable prognosis for patients with SPOPmut PC. In metastatic settings, SPOP mutations correlated with improved progression-free survival (PFS) and OS in patients undergoing androgen deprivation therapy ± androgen receptor signaling inhibitor (HR: 0.51, 95% CI: 0.35-0.76, p < 0.01, and HR: 0.60, 95% CI:0.46-0.79, p < 0.01, respectively). In metastatic castration-resistant PC, only abiraterone provided improved PFS and OS to patients with SPOP mutations compared with patients with SPOPwt, but data were limited. SPOP mutations did not correlate with improved PFS (p = 0.80) or OS (p = 0.27) for docetaxel. CONCLUSIONS: Patients with SPOPmut PC seem to exhibit superior oncological outcomes compared with patients with SPOPwt. Tailored risk stratification and treatment approaches should be explored in such patients. PATIENT SUMMARY: Speckle-type POZ (SPOP) mutations could be a favorable prognostic factor in patients with prostate cancer (PC) and may also predict better progression-free and overall survival than treatment with hormonal agents. Therefore, less intensified treatments omitting chemotherapy for patients with SPOP-mutant PC should be explored in clinical trials.
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BACKGROUND: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1ß production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1ß and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1ß, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.
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Progresión de la Enfermedad , Fosfohidrolasa PTEN , Neoplasias de la Próstata , Microambiente Tumoral , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Animales , Ratones , Humanos , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Microambiente Tumoral/inmunología , Fenotipo Secretor Asociado a la Senescencia , Proteínas Proto-Oncogénicas c-jun/metabolismo , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Perfilación de la Expresión Génica , Senescencia Celular/genética , Modelos Animales de EnfermedadRESUMEN
CONTEXT: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in most prostate cancers and exploited as a target for PSMA-targeted therapies. Different approaches to target PSMA-expressing cancer cells have been developed, showing promising results in clinical trials. OBJECTIVE: To discuss the regulation of PSMA expression and the main PSMA-targeted therapeutic concepts illustrating their clinical development and rationalizing combination approaches with examples. EVIDENCE ACQUISITION: We performed a detailed literature search using PubMed and reviewed the American Society of Clinical Oncology and European Society of Medical Oncology annual meeting abstracts up to September 2023. EVIDENCE SYNTHESIS: We present an overarching description of the different strategies to target PSMA. The outcomes of PSMA-targeted therapies strongly rely on surface-bound PSMA expression. However, PSMA heterogeneity at different levels (interpatient and inter/intratumoral) limits the efficacy of PSMA-targeted therapies. We highlight the molecular mechanisms governing PSMA regulation, the understanding of which is crucial to designing therapeutic strategies aimed at upregulating PSMA expression. Thus far, homeobox B13 (HOXB13) and androgen receptor (AR) have emerged as critical transcription factors positively and negatively regulating PSMA expression, respectively. Furthermore, epigenetic regulation of PSMA has been also reported recently. In addition, many established therapeutic approaches harbor the potential to upregulate PSMA levels as well as potentiate DNA damage mediated by current radioligands. CONCLUSIONS: PSMA-targeted therapies are rapidly advancing, but their efficacy is strongly limited by the heterogeneous expression of the target. A thorough comprehension of how PSMA is regulated will help improve the outcomes through increasing PSMA expression and will provide the basis for synergistic combination therapies. PATIENT SUMMARY: Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancers. PSMA-targeted therapies have shown promising results, but the heterogeneous expression of PSMA limits their efficacy. We propose to better elucidate the regulation of PSMA expression to increase the levels of the target and improve the therapeutic outcomes.
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Próstata , Neoplasias de la Próstata , Masculino , Humanos , Próstata/metabolismo , Epigénesis Genética , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Antígenos de Superficie , Antígeno Prostático Específico/genética , Resultado del TratamientoRESUMEN
The evolutionarily conserved minor spliceosome (MiS) is required for protein expression of â¼714 minor intron-containing genes (MIGs) crucial for cell-cycle regulation, DNA repair, and MAP-kinase signaling. We explored the role of MIGs and MiS in cancer, taking prostate cancer (PCa) as an exemplar. Both androgen receptor signaling and elevated levels of U6atac, a MiS small nuclear RNA, regulate MiS activity, which is highest in advanced metastatic PCa. siU6atac-mediated MiS inhibition in PCa in vitro model systems resulted in aberrant minor intron splicing leading to cell-cycle G1 arrest. Small interfering RNA knocking down U6atac was â¼50% more efficient in lowering tumor burden in models of advanced therapy-resistant PCa compared with standard antiandrogen therapy. In lethal PCa, siU6atac disrupted the splicing of a crucial lineage dependency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers.
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Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Intrones/genética , Neoplasias de la Próstata/metabolismo , Empalme del ARN/genética , Empalmosomas/metabolismo , Transducción de Señal , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Línea Celular Tumoral , Neoplasias de la Próstata Resistentes a la Castración/genéticaRESUMEN
Comprehensive cancer genome studies have revealed genetically-defined subtypes of prostate cancer with distinct truncal driver mutations. Because prostate cancer has been largely seen as a rather uniform disease, the clinical significance of this discovery remained largely obscure. However, recent findings imply distinct biological features and therapeutic vulnerabilities linked to specific truncal mutations. Here we review our current understanding of prostate cancers harboring recurrent point mutations in the ubiquitin ligase adaptor protein SPOP and discuss opportunities for future clinical translation. More specifically, activation of the androgen receptor (AR) signaling emerges as the key oncogenic pathway. SPOP-mutant prostate cancer patients respond to AR inhibition in various clinical settings. Molecular insights on how mutant SPOP promotes tumorigenesis may open more specific therapeutic avenues which, in combination with conventional AR-targeting agents, could improve the outcome of patients with SPOP-mutant prostate cancer.
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Biomarcadores de Tumor , Mutación , Proteínas Nucleares/genética , Neoplasias de la Próstata/etiología , Proteínas Represoras/genética , Alelos , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Mutación con Pérdida de Función , Masculino , Modelos Biológicos , Modelos Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Atención al Paciente , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Conformación Proteica , Proteínas Represoras/química , Proteínas Represoras/metabolismo , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Comprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory - reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression.
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Proteína Potenciadora del Homólogo Zeste 2/genética , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , Transcriptoma , Animales , Atlas como Asunto , Línea Celular Tumoral , Progresión de la Enfermedad , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Proteínas de Neoplasias/metabolismo , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Análisis de Componente Principal , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transducción de Señal , Análisis de la Célula IndividualRESUMEN
The availability of L-arginine in tumours is a key determinant of an efficient anti-tumour T cell response1-4. Consequently, increases of typically low L-arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies5. However, currently no means are available to locally increase intratumoural L-arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours6, to L-arginine. Colonization of tumours with these bacteria increased intratumoural L-arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies.
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Inmunoterapia/métodos , Ingeniería Metabólica , Microorganismos Modificados Genéticamente , Neoplasias Experimentales/terapia , Traslado Adoptivo , Animales , Arginina/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Línea Celular Tumoral , Escherichia coli , Femenino , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/microbiología , Probióticos , Proteoma , Biología Sintética , Linfocitos T/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.
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Andrógenos/biosíntesis , Bacterias/metabolismo , Microbioma Gastrointestinal/fisiología , Interacciones Microbiota-Huesped , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/microbiología , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Animales , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Bacterias/genética , Línea Celular Tumoral , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Neoplasias Experimentales , Prevotella/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Simbiosis , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cancer is the dysregulated proliferation of cells caused by acquired mutations in key driver genes. The most frequently mutated driver genes promote tumorigenesis in various organisms, cell types, and genetic backgrounds. However, recent cancer genomics studies also point to the existence of context-dependent driver gene functions, where specific mutations occur predominately or even exclusively in certain tumor types or genetic backgrounds. Here, we review examples of co-occurring and mutually exclusive driver gene mutation patterns across cancer genomes and discuss their underlying biology. While co-occurring driver genes typically activate collaborating oncogenic pathways, we identify two distinct biological categories of incompatibilities among the mutually exclusive driver genes depending on whether the mutated drivers trigger the same or divergent tumorigenic pathways. Finally, we discuss possible therapeutic avenues emerging from the study of incompatible driver gene mutations.
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Algoritmos , Neoplasias , Carcinogénesis/genética , Genómica , Humanos , Mutación , Neoplasias/genéticaRESUMEN
Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.
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Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Neoplasias de la Próstata/metabolismo , Proteínas Represoras/metabolismo , Regulador Transcripcional ERG/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Humanos , Inmunohistoquímica , Inmunoprecipitación , Masculino , Ratones , Ratones Desnudos , Mutación/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Neoplasias de la Próstata/genética , Unión Proteica , Proteómica , Receptores Androgénicos/metabolismo , Proteínas Represoras/genética , Transducción de Señal/fisiología , Regulador Transcripcional ERG/genética , Complejos de Ubiquitina-Proteína Ligasa/genéticaRESUMEN
Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
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Modelos Biológicos , Organoides/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Andrógenos/metabolismo , Antineoplásicos/uso terapéutico , Genoma Humano , Humanos , Masculino , Mutación/genética , Metástasis de la Neoplasia , Neoplasias de la Próstata/genética , Transcriptoma/genéticaRESUMEN
Targeting the androgen receptor (AR) signaling axis has been, over decades, the mainstay of prostate cancer therapy. More potent inhibitors of androgen synthesis and antiandrogens have emerged and have been successfully implemented in clinical practice. That said, the stronger inhibition of the AR signaling axis has led in recent years to an increase of prostate cancers that de-differentiate into AR-negative disease. Unfortunately, this process is intimately linked with a poor prognosis. Here, we review the molecular mechanisms that enable cancer cells to switch from an AR-positive to an AR-negative disease and efforts to prevent/revert this process and thereby maintain/restore AR-dependence.
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Andrógenos/genética , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Andrógenos/biosíntesis , Humanos , Masculino , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Transducción de Señal/genéticaRESUMEN
Extracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients. Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH. Release of miR-424 in small EVs was enhanced in cell lines (LNCaPabl), transgenic mice (Pb-Cre4;Ptenflox/flox;Rosa26ERG/ERG) and patient-derived xenograft (PDX) models of aggressive disease. EVs containing miR-424 promoted stem-like traits and tumor-initiating properties in normal prostate epithelial cells while enhanced tumorigenesis in transformed prostate epithelial cells. Intravenous administration of miR-424 positive EVs to mice, mimicking blood circulation, promoted miR-424 transfer and tumor growth in xenograft models. Circulating miR-424 positive EVs from patients with aggressive primary and metastatic tumors induced stem-like features when supplemented to prostate epithelial cells. This study establishes that EVs-mediated transfer of miR-424 across heterogeneous cell populations is an important mechanism of tumor self-sustenance, disease recurrence and progression. These findings might indicate novel approaches for the management and therapy of prostate cancer.
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Transformación Celular Neoplásica/genética , Micropartículas Derivadas de Células/metabolismo , Vesículas Extracelulares/metabolismo , MicroARNs/metabolismo , Neoplasias de la Próstata , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Micropartículas Derivadas de Células/genética , Vesículas Extracelulares/genética , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , MicroARNs/genética , Modelos Teóricos , Invasividad Neoplásica , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
In the context of dysregulated ubiquitylation, the accumulation of oncogenic substrates can lead to tumorigenesis. In particular, mutations in Von Hippel-Lindau (VHL) E3 ubiquitin ligase are related to overexpression of hypoxia-inducible factors (HIF-1α and HIF-2α) which is evolving into renal cell carcinoma (RCC). The classical approach of drug discovery focuses on the development of highly selective small molecules able to bind and to inhibit enzymatic active sites. This strategy faces limitations in the context of ' undruggable ' proteins, which are challenging to target. The discovery of Proteolysis Targeting Chimeras (PROTACs) as an alternative strategy to induce selective protein degradation is presented as a working hypothesis to understand further the UbiquitinProteasome System (UPS) and eventually counteract RCC cancer lacking VHL ubiquitin ligase.
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Complejo de la Endopetidasa Proteasomal , Ubiquitina , Péptidos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas , Proteína Supresora de Tumores del Síndrome de Von Hippel-LindauRESUMEN
Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by utilizing a gene co-expression network of transcriptomics data in addition to laser-microdissected proteomics from human and murine prostate FFPE samples. We show up-regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up-regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis.
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Perfilación de la Expresión Génica/métodos , Recurrencia Local de Neoplasia/genética , Neoplasias Experimentales/patología , Neoplasias de la Próstata/genética , Proteómica/métodos , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Factor de Transcripción STAT3/genética , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Captura por Microdisección con Láser , Masculino , Ratones , Clasificación del Tumor , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Fosforilación Oxidativa , Pronóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Factor de Transcripción STAT3/metabolismo , Biología de Sistemas , Adulto JovenRESUMEN
The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti-CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.
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Antígenos de Neoplasias/biosíntesis , Moléculas de Adhesión Celular/biosíntesis , Regulación Neoplásica de la Expresión Génica , Sistema de Señalización de MAP Quinasas , Neoplasias de la Próstata/metabolismo , Regulación hacia Arriba , Animales , Antígenos de Neoplasias/genética , Benzamidas , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Drosophila melanogaster , Humanos , Liposomas , Masculino , Nitrilos , Fosfohidrolasa PTEN/biosíntesis , Fosfohidrolasa PTEN/genética , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
Prostate cancer (PCa) is the second leading cause of cancer death in men. Its clinical and molecular heterogeneities and the lack of in vitro models outline the complexity of PCa in the clinical and research settings. We established an in vitro mouse PCa model based on organoid technology that takes into account the cell of origin and the order of events. Primary PCa with deletion of the tumor suppressor gene PTEN (PTEN-del) can be modeled through Pten-down-regulation in mouse organoids. We used this system to elucidate the contribution of TIP5 in PCa initiation, a chromatin regulator that is implicated in aggressive PCa. High TIP5 expression correlates with primary PTEN-del PCa and this combination strongly associates with reduced prostate-specific antigen (PSA) recurrence-free survival. TIP5 is critical for the initiation of PCa of luminal origin mediated by Pten-loss whereas it is dispensable once Pten-loss mediated transformation is established. Cross-species analyses revealed a PTEN gene signature that identified a group of aggressive primary PCas characterized by PTEN-del, high-TIP5 expression, and a TIP5-regulated gene expression profile. The results highlight the modeling of PCa with organoids as a powerful tool to elucidate the role of genetic alterations found in recent studies in their time orders and cells of origin, thereby providing further optimization for tumor stratification to improve the clinical management of PCa.
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Proteínas Cromosómicas no Histona/metabolismo , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata/metabolismo , Animales , Carcinogénesis , Transformación Celular Neoplásica , Proteínas Cromosómicas no Histona/genética , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Noqueados , Fosfohidrolasa PTEN/metabolismo , Próstata/metabolismo , Neoplasias de la Próstata/genéticaRESUMEN
Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms.
Asunto(s)
Mutación Missense , Trastornos del Neurodesarrollo/genética , Proteínas Nucleares/genética , Proteínas Represoras/genética , Adolescente , Niño , Preescolar , Facies , Femenino , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Cráneo/anomalías , Adulto JovenRESUMEN
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.