Prostate Cancer Metastasis Research Articles

Cancer-associated fibroblast-secreted exosomes promote prostate cancer cell migration and invasion by the FGL1/SOX5 axis.

Exosomes secreted by cancer-associated fibroblasts (CAFs) play a critical role in cancer progression. This study aimed to explore the effects of CAF exosomes on prostate cancer (PC) cell metastasis. PC cells were treated with these exosomes, and their processes were evaluated using cell-counting kit-8 and Transwell assays. Exosome-regulated mRNAs were explored using quantitative real-time PCR. The relationship between FGL1 and SOX5 was analyzed using co-immunoprecipitation and fluorescence in situ hybridization (FISH) assays. The results of this study showed that exosomes derived from CAFs promoted PC cell viability, migration, and invasion. CAFs promoted PC cell viability and metastasis by releasing exosomes. Exosome treatment increased the levels of FGL1, which interacted with SOX5 and negatively regulated its expression. Rescue experiments demonstrated that CAF exosomes promoted the biological behaviors of PC cells by upregulating FGL1 and downregulating SOX5. Moreover, exosomes accelerated tumor growth by regulating the FGL1 level. In conclusion, CAF-derived exosomes promoted PC cell viability, migration, and invasion by elevating the FGL1/SOX5 axis, suggesting a novel strategy for the treatment of metastatic PC.

Melatonin Inhibits ET-1 Production to Break Crosstalk Between Prostate Cancer and Bone Cells: Implication for Osteoblastic Bone Metastasis Treatment.

Bone metastasis is the primary cause of death among patients with advanced prostate cancer (PCa). PCa tends to spread to bones and acquire the bone-like phenotype, causing osteoblastic bone metastasis. Unfortunately, there is no effective treatment for this condition. However, melatonin, which regulates our circadian rhythm, has been found to have anti-tumor properties. It has yet to be established whether it is effective in treating osteoblastic PCa metastasis. Our findings show that melatonin inhibits the production of endothelin-1 (ET-1) in osteoblastic PCa cells, suppressing osteoblast differentiation. Clinical results indicate that bone metastatic PCa patients have higher levels of ET-1 compared to nonmetastatic PCa patients. Furthermore, melatonin-induced miR-let-7f-5p inhibits ET-1-promoted osteoblast differentiation in osteoblastic PCa. Melatonin also suppresses the property of osteomimicry in osteoblastic PCa cells. Importantly, in the intratibia injection PCa metastasis model, melatonin decreased osteoblastic PCa tumor growth, inhibiting ET-1 production and osteoblast differentiation in vivo. Taken together, melatonin inhibits osteoblastic PCa-regulated osteoblastogenesis by reducing ET-1 production through upregulation of miR-let-7f-5p, while suppressing the property of osteomimicry in osteoblastic PCa. Melatonin therapy could be a promising approach to treating bone metastasis in osteoblastic PCa.

S3904 Rare Metastasis of Prostate Cancer in a Male With Ulcerative Colitis Following Creation of an Ileal Pouch

S3904 Rare Metastasis of Prostate Cancer in a Male With Ulcerative Colitis Following Creation of an Ileal Pouch

The role of Cabazitaxel in patients with castration-resistant and osseous metastases prostate cancer. A Hellenic Cooperative Oncology Group Phase II Study.: Cabazitaxel in mCRPC patients with osseous metastases

BackgroundCabazitaxel is an effective treatment in metastatic castration-resistant prostate cancer (mCRPC) patients previously exposed to docetaxel and novel hormonal treatments. Understanding the molecular biology of mCRPC disease and taking into account the several approved treatment options, biomarkers are needed to guide decision making including cabazitaxel treatment. MethodsCababone was a phase II translational study that attempted to identify predictors of cabazitaxel efficacy. mCRPC with documented bone metastases were enrolled prospectively and treated with cabazitaxel 25mg/m2 every three weeks. Prostate cancer biopsies, bone marrow aspirates and blood samples were collected for translational research. ResultsSixty patients were enrolled and 59 received treatment according to protocol. Six-month progression free survival (PFS) rate was 47% (95% CI: 33% - 59%) and 12-month Overall Survival (OS) rate was 70% (95% CI: 56% - 80%). Patients with reactive hematopoiesis had improved PFS and OS with cabazitaxel treatment. Mutations in HRR genes were detected in 7 patients. ConclusionsNo differences in cabazitaxel efficacy were noted according to mutational status of HRR genes analyzed. No new safety issues were detected. In conclusion, CabaBone confirmed efficacy of cabazitaxel in mCRPC patients including the subgroup of patients with HRR mutations. Reactive hematopoiesis in bone marrow biopsies was related to improved survival warranting further investigation of bone biomarkers as predictors of cabazitaxel efficacy. Micro-AbstactCabaBone is a phase II translational study that evaluated the role of bone microenvironment and HRR genes mutations in the efficacy of cabazitaxel in mCRPC patients with bone-only disease. Study confirmed efficacy of cabazitaxel in patients independent of the presence of HRR gene mutations. Reactive hematopoiesis in bone marrow was recognized as a possible predictive and prognostic biomarker of cabazitaxel efficacy.

Insight into prostate cancer osteolytic metastasis by RelB coordination of IL-8 and S100A4.

Although RANK-LRANK interaction is essential for osteoclastogenesis, the mechanisms by which cancer cells invade bone tissues and initiate osteolytic metastasis remain unclear. Here, we show that the hyperactivation of RelB fosters prostate cancer (PCa) osteolytic metastasis by coordinating interleukin-8 (IL-8) and calcium-binging protein A4 (S100A4). The factors promoting PCa bone metastasis were investigated in sera from PCa patients and tumour tissues derived from nude mice using immunohistochemical analysis and enzyme-linked immunosorbent assays (ELISA). Cell mobility and mineralization were quantified using BioStation CT and Osteolmage assay. The relative cistrome was investigated in advanced PCa cells by standard transcriptional analyses, including the luciferase reporter response, site-directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay. PCa cell-initiated tumour formation, expansion, and bone metastasis were validated in mice using multiple approaches, including orthotopic, intraskeletal, and caudal arterial implantation models. IL-8 and S100A4 correlated with patient Gleason scores and bone metastasis. RelB upregulated IL-8, facilitating androgen receptor (AR)-independent growth. RelB-Sp1 interaction enhanced epithelial-mesenchymal transition (EMT) by activating Snail and Twist. RelB-NFAT1c super-enhancer upregulated S100A4 in the organization of the cytoskeleton and bone metastasis. The RelB-IL-8-S100A4 signalling axis was confirmed to promote osteolytic metastasis in nude mice. RelB-IL-8 reciprocally promoted EMT by activating inflammatory signalling and inactivating AR signalling. IL-8 is essential for provoking PCa metastasis but insufficient to drive bone metastasis. IL-8-S100A4 cooperation was necessary for metastatic cells to target the bone. RelB activates inflammatory signalling by upregulating IL-8 and suppressing AR. RelB upregulates S100A4 by cooperating with NFATC1. IL-8 boosts EMT by activating Snail 1 and Twist 1, and S100A4 exacerbates osteolytic metastasis via calcium consumption. RelB harnesses IL-8 and S100A4 to drive PCa osteolytic metastasis.

Epidural Analgesia for Palliative Pain Management for A Patient with An Advanced Stage Prostate Cancer: A Case Report

Introduction: Patients with advanced-stage cancer should be able to stay at home with their families without suffering from pain. This case report aims to discuss challenges in pain management of a patient with bone metastasis of prostate cancer who received epidural analgesia at home. Challenges were related to the patients, health professionals, and system. Understanding each factor will bring insights to develop a workable pain management program in the palliative setting. Case Presentation: A 66-year-old male was diagnosed with left sacroiliac joint pain due to metastatic prostate cancer. After a three-year history of prostate cancer and ineffective chemotherapy, the patient complained of pain in the left hip that did not improve with conventional medications (paracetamol, tramadol, and Morphine Sustained Release/MST). In response, the consideration of an epidural implant emerged as a potential solution, offering the prospect of home-based care and autonomous medication administration through an epidural continuous block with intermittent drug injection. Conclusions: This case highlights home-based interventional pain management for cancer, addressing challenges at the patient, health professional, and system level. Overcoming these challenges requires a multidisciplinary approach and robust institutional policies. The insights gained offer valuable lessons for hospitals aiming to enhance the competence of pain and palliative care teams and establish comprehensive support systems in hospital and home settings.

Nuclear receptor TLX functions to promote cancer stemness and EMT in prostate cancer via its direct transactivation of CD44 and stem cell-regulatory transcription factors.

Prostate cancer stem cells (PCSCs) play crucial roles in therapy-resistance and metastasis in castration-resistant prostate cancer (CRPC). Certain functional link between cancer stemness and epithelial-mesenchymal transition (EMT) is involved in CRPC. However, up-stream regulators controlling these two processes in PCSCs are still poorly understood. Recently, we have shown that orphan nuclear receptor TLX can promote tumour initiation and progression in CRPC by repressing androgen receptor and oncogene-induced senescence. PCSCs were isolated from various prostate cancer cell lines and clinical tumour tissues using multiple methods for various in vitro and in vivo oncogenic growth analyses. Direct targets of TLX involved in stemness and EMT regulation were determined by specific reporter gene assays and ligand-driven modulation of TLX activity. PCSCs isolated from various sources exhibited increased expression of TLX. Functional and molecular characterisation showed that TLX could function to promote cancer stemness and EMT in prostate cancer cells via its direct transactivation of CD44, SOX2, POU5F1 and NANOG, which share certain functional crosstalk in these two cellular processes. TLX could act as a key up-stream regulator in transcriptional control of stemness and EMT in PCSCs, which contribute to their tumorigenicity, castration-resistance and metastasis potentials in advanced prostate cancer.

Exosomes are the mediators between the tumor microenvironment and prostate cancer (Review).

Prostate cancer poses a serious threat to the well-being of men worldwide, with the leading cause of mortality being primarily through metastasis. Prostate cancer metastasis is dependent on cell communication, which is an essential component of this process; yet its exact mechanism remains obscure. Nonetheless, cell-to-cell communication plays a critical part in prostate cancer metastasis. Exosomes play an indispensable role in the development of metastatic growth by promoting intercellular communication. They are pivotal regulatory agents for both prostate cancer cells as well as their microenvironment. The present study investigated the makeup and function of exosomes in the tumor microenvironment, highlighting their significance to prostate cancer metastasis.

Stereotactic radiosurgery for patients with spinal metastases from prostate cancer.

Spinal metastases may result in intractable pain, neurological deficit, and vertebral body collapse. There are only a few studies describing outcomes following spine stereotactic radiosurgery (SRS) specifically for prostate cancer metastases. A prospectively collected database of patients with prostate cancer spinal metastases treated at the University of Pittsburgh Medical Center from 2003 to 2023 was analyzed. The primary outcome was local control (LC). Secondary outcomes were overall survival (OS), pain resolution, and adverse radiation effects (AREs). Thirty-seven patients and 51 lesions were identified. Fifteen lesions (29%) were previously resected and 34 lesions (67%) were previously irradiated. The median tumor volume was 37.0cc (range: 2.9-263.3). A majority of lesions (71%) were treated in a single fraction (median 20Gy, range: 14-22.5); multi-fractionated treatment consisted of 21-30Gy in 2-5 fractions. Median follow-up was 12 months (range: 1-146). The 6-month, 1-year, and 2-year LC rates were 97%, 91%, and 91%, respectively. No tested prognostic factors were associated with LC, including hormone sensitivity. The 6-month, 1-year, and 2-year OS rates were 71%, 56%, and 32%; age > 70 years (p = 0.048) and tumor volume > 30cc (p = 0.03) were associated with inferior rates of OS. Complete or partial pain response was observed in 58% of patients. There were 8 instances (16%) of AREs, 2 of which were vertebral compression fractures (4%). Radiosurgery as a primary or adjuvant treatment modality for prostate cancer spinal metastases confers durable LC and moderate pain relief with minimal toxicity. Further studies are warranted to optimize management in this patient population.

Abstract A031: Methylomic Biomarkers Associated with Prostate Cancer in Black Men

Abstract Introduction: The prostate cancer (PCa) disparity remains the highest cancer disparity in the US, with Black men facing an estimated 78% higher incidence and 230% higher mortality than White men. However, current understanding of risk factors for PCa such as socioeconomic status (SES), diet, and genetics cannot fully explain these disparities. Our objective is to examine DNA methylation (DNAm) markers in a cohort of Black men and assess their associations with PCa status. Methods: We randomly selected 100 Black men for DNAm profiling (50 cases diagnosed with clinically significant (Gleason Grade 3+) prostate cancer and 50 age-matched controls) from two larger cohorts. The cohorts recruited 400 Black men who were newly diagnosed with sporadic PCa as well as 400 controls matched on age and race. All men were 40-79 at recruitment and were enrolled from urology clinics at five Chicago-area medical institutions. All PCa cases underwent a transrectal prostate biopsy for abnormal prostate-specific antigen (PSA) or digital rectal exam and had a histologically confirmed prostate cancer and were not previously diagnosed with PCa. All men in the control group had been recruited from community prostate cancer screening events or were referred to participating urology clinics and had a negative prostate biopsy for a PSA <10ng/ml and were not diagnosed with PCa for 2 years of follow-up. Men with prior PCa diagnosis or conditions known to affect PSA levels were excluded. After enrollment and informed consent, all men provided demographic and lifestyle data via three questionnaires, followed by venipuncture for DNA collection. These specimens were obtained using buffy coat extraction after red blood cell lysis, centrifugation, and pipetting off the overlying plasma and buffy coat for freezing followed by Illumina EPIC arrays for DNAm assays. We examined DNAm markers in gene promoter regions associated with PCa using logistic regression and adjusted for multiple testing using Bonferroni correction. All models controlled for age, BMI, smoking status, first degree family history of PCa, blood cell types, and technical control variables. Results: We found 2,180 CpG sites in gene promoter regions associated with any PCa in this population. The top ten strongest associations identified in our models include loci on genes that have already been associated with prostate cancer progression (MAFG, FAM65B, OSM, PRKAG2), risk (SLC11A1, LAT), and metastasis (S1PR4) as well as immune system functioning (RAP1GAP2). Conclusions: Our initial findings suggest that DNAm markers may be useful predictors of clinically significant PCa status among Black men. Additional research is currently ongoing to expand the sample size of the DNAm profiling and to explore links between these loci and social determinants of health, as well as associations with more advanced (i.e., higher Gleason Grade) PCa. Citation Format: Brian T. Joyce, Yishu Qu, Jun Wang, Kai Zhang, Zequn Sun, Lifang Hou, Adam B. Murphy. Methylomic Biomarkers Associated with Prostate Cancer in Black Men [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A031.

Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review).

The incidence of prostate cancer (PCa) is increasing, making it one of the prevalent malignancies among men. Metastasis of PCa to the bones poses the greatest danger to patients, potentially resulting in treatment ineffectiveness and mortality. At present, the management of patients with bone metastasis focuses primarily on providing palliative care. Research has indicated that the spread of PCa to the bones occurs through the participation of numerous molecules and their respective pathways. Gaining knowledge regarding the molecular processes involved in bone metastasis may result in the development of innovative and well‑tolerated therapies, ultimately enhancing the quality of life and prognosis of patients. The present article provides the latest overview of the molecular mechanisms involved in the formation of bone metastatic tumors from PCa. Additionally, the clinical outcomes of targeted drug therapies for bone metastasis are thoroughly analyzed. Finally, the benefits and difficulties of targeted therapy for bone metastasis of PCa are discussed, aiming to offer fresh perspectives for treatment.

The Contribution of 68Ga Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography Imaging to Detecting Brain Metastasis in Prostate Cancer

The Contribution of 68Ga Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography Imaging to Detecting Brain Metastasis in Prostate Cancer

Comprehensive scRNA-seq analysis to identify new markers of M2 macrophages for predicting the prognosis of prostate cancer

Background Prostate cancer (PCa) has become the highest incidence of malignant tumor among men in the world. Tumor microenvironment (TME) is necessary for tumor growth. M2 macrophages play an important role in many solid tumors. This research aimed at the role of M2 macrophages’ prognosis value in PCa. Methods Single-cell RNA-seq (scRNA-seq) data and mRNA expression data were obtained from the Gene Expression Omnibus database (GEO) and The Cancer Genome Atlas (TCGA). Quality control, normalization, reduction, clustering, and cell annotation of scRNA-seq data were preformed using the Seruat package. The sub-populations of the tumor-associated macrophages (TAMs) were analysis and the marker genes of M2 macrophage were selected. Differentially expressed genes (DEGs) in PCa were identified using limma and the immune infiltration was detected using CIBERSORTx. Then, a weighted correlation network analysis (WGCNA) was constructed to identify the M2 macrophage-related modules and genes. Integration of the marker genes of M2 macrophage from scRNA-seq data analysis and hub genes from WGCNA to select the prognostic gene signature based on Univariate and LASSO regression analysis. The risk score was calculated, and the DEGs, biological function, immune characteristics related to risk score were explored. And a predictive nomogram was constructed. CCK8, Transwell, and wound healing were used to verify cell phenotype changes after co-cultured. Results A total of 2431 marker genes of M2 macrophage and 650 hub M2 macrophage-related genes were selected based on scRNA-seq data and WGCNA. Then, 113 M2 macrophage-related genes were obtained by overlapping the scRNA-seq data and WGCNA results. Nine M2 macrophage-related genes (SMOC2, PLPP1, HES1, STMN1, GPR160, ABCG1, MAZ, MYC, and EPCAM) were screened as prognostic gene signatures. M2 risk score was calculated, the DEGs, Immune score, stromal score, ESTIMATE score, tumor purity, and immune cell infiltration, immune checkpoint expression, and responses of immunotherapy and chemotherapy were identified. And a predictive nomogram was constructed. CCK8, Transwell invasion, and wound healing further verified that M2 macrophages promoted the proliferation, invasion, and migration of PCa (p < 0.05). Conclusions We uncovered that M2 macrophages and relevant genes played key roles in promoting the occurrence, development, and metastases of PCa and played as convincing predictors in PCa.

Curcumin blunts epithelial-mesenchymal transition to alleviate invasion and metastasis of prostate cancer through the JARID1D demethylation

Prostate cancer (PCa) is one of the most common and prevalent cancers in men worldwide. The majority of PCa-related deaths result from metastasis rather than primary tumors. Several studies have focused on the relationship between male-specific genes encoded on the Y chromosome and PCa metastasis; however, the relationship between the male specific protein encoded on the Y chromosome and tumor suppression has not been fully clarified. Here, we report a male specific protein of this type, the histone H3 lysine 4 (H3K4) demethylase JARID1D, which has the ability to inhibit the gene expression program related to cell invasion, and can thus form a phenotype that inhibits the invasion of PCa cells. However, JARID1D exhibits low expression level in advanced PCa, and which is related to rapid invasion and metastasis in patients with PCa. Curcumin, as a multi-target drug, can enhance the expression and demethylation activity of JARID1D, affect the androgen receptor (AR) and epithelial-mesenchymal transition (EMT) signaling cascade, and inhibit the metastatic potential of castration resistant cancer (CRPC). These findings suggest that using curcumin to increase the expression and demethylation activity of JARID1D may be a feasible strategy to inhibit PCa metastasis by regulating EMT and AR.

Prevalence and management of castration-resistant prostate cancer of unknown metastatic status in the real-world setting: The AfroDiTA study

BackgroundEarly identification and management of metastases in prostate cancer (PC) patients is crucial. This study aimed to describe the nonpharmacological management and characteristics of patients with castration-resistant PC with unknown metastatic status (CRPC-MX) and estimate their prevalence in Spain. MethodsCross-sectional, multicenter, real-world study including adult (≥18 years) CRPC-MX patients from 46 Urology services. In a first phase, patients on continuous ADT for ≥6 months were screened and classified as hormone-sensitive PC (HSPC), castration-resistant PC (CRPC), and unknown hormonal status, with metastases (M1), without (M0) and unknown metastatic status (MX) using an ad hoc designed algorithm. In Phase 2, 15 months (m) after Phase 1, all patients on ADT were reviewed and reclassified again using the algorithm. ResultsAmong 6169 eligible PC patients, 294 (4.8%) were classified as CRPC-MX, which decreased to 179 of 4050 (4.4%) 15 m after study initiation. We included 103 CRPC-MX patients with a median age at diagnosis of 75.4 years (IQR: 67.8, 80.4); 26 (25.2%) lacked a histological diagnosis, and only 25 (24.5%) received treatment with curative intent, despite ECOG being ≤1 at inclusion in 83.5%. In the 15 m before inclusion, most CRPC-MX patients had <5 prostate-specific antigen (PSA) determinations (80.6%) and no imaging (63.1%). After CRPC-MX identification (15 m after inclusion), metastatic status was assessed in 55.4%, with an increased number of patients with ≥5 PSA determinations (P = 0.0357), visits per patient (P < 0.0001), patients with some imaging test (P < 0.0001), imaging tests/patient (P < 0.0001), and visits to onco-urology specialized consultation units (52.0% before and 79.2% after). ConclusionA substantial proportion of PC patients on ADT in the real-world setting are not appropriately followed up. Identification of CRPC-MX patients raised awareness among physicians and improved their adherence to guidelines, resulting in improved care for these patients.

Association between 99mTc-PSMA SPECT/CT imaging and prostate-specific antigen (PSA) and alkaline phosphatase (ALP) levels post-endocrine therapy in patients with prostate cancer and bone metastases

AimTo investigate the association between positive lesions detected by 99mTc-PSMA SPECT/CT and blood levels of prostate-specific antigen (PSA) and alkaline phosphatase (ALP) in patients with prostate cancer (PCa) and bone metastasis undergoing endocrine therapy. MethodsA retrospective analysis was performed on 43 patients diagnosed with PCa bone metastasis who underwent endocrine therapy. PSA, ALP, whole body bone imaging and 99mTc-PSMA SPECT/CT imaging were collected from all patients (Among them, 17 cases were re-examined 99mTc-PSMA SPECT/CT imaging). According to the results of the first 99mTc-PSMA SPECT/CT imaging for detecting bone metastasis, all cases were divided into two groups: positive group and negative group. The relationship between 99mTc-PSMA imaging and PSA and ALP was analyzed by ROC curve. Fisher exact probability method was used to examine the changes in imaging radioactivity uptake, PSA, and ALP levels in 17 patients after treatment, and P < 0.05 was statistically significant. ResultsAll 43 patients had different degrees of radioactive concentrations on whole-body bone imaging. The first 99mTc-PSMA SPECT/CT imaging showed positive bone metastases in 31 cases and negative bone metastases in 12 cases. ROC curve analysis of PSA and ALP, AUC were 0.778 and 0.770, respectively. When PSA > 1.13 ng/mL, 99mTc-PSMA SPECT/CT imaging diagnostic sensitivity was 93.55%, and specificity was 66.67%. When ALP was >86U/L, the diagnostic sensitivity of 99mTc-PSMA SPECT/CT imaging was 64.52%, and the specificity was 83.33%. In 17 cases, the PSA level decreased in 7 and increased in 10. There were 10 cases of increased ALP and 7 cases of decreased ALP levels. In the second 99mTc-PSMA imaging lesion, there were 9 cases with decreased or no uptake, and 8 cases with increased uptake or number of lesions. The changes in 99mTc-PSMA uptake by Fisher’s exact probability method were statistically significant (P < 0.05, P = 0.006, and P = 0.006, respectively), and ALP level was not statistically significant (P = 0.563). Conclusion99mTc-PSMA SPECT/CT imaging can detect PCa bone metastases, which are related to PSA levels. When PSA > 1.13 ng/mL, the sensitivity of diagnosis and detection of positive bone metastases is higher, and when ALP is >86U/L, 99mTc-PSMA imaging has higher specificity.

Prevention of prostate cancer metastasis by a CRISPR-delivering nanoplatform for interleukin-30 genome editing

Prostate-cancer (PC) is a leading cause of cancer-related deaths in men worldwide. Interleukin-(IL)-30 is a PC-progression driver, and its suppression would be strategic for fighting metastatic disease. Biocompatible Lipid-Nanoparticles (NPs) were loaded with CRISPR/Cas9gRNA to delete human(h)IL30-gene and functionalized with anti-PSCA-Abs (Cas9hIL30-PSCA-NPs). Efficiency of the NPs in targeting IL30 and metastatic potential of PC cells was examined in vivo, in xenograft models of lung metastasis, and in vitro, by using 2-Organ-on-Chip (2-OC), containing 3D-spheroids of IL30+PC-Endothelial-Cell(EC) co-cultures in circuit with either Lung-mimicking-spheroids, or Bone-marrow(BM)-niche-mimicking-scaffolds. Cas9hIL30-PSCA-NPs demonstrated circulation stability, genome editing efficiency, without off-target effects and organ toxicity. Intravenous injection of three-doses/13-days, or five-doses/20-days, of NPs in mice bearing circulating PC cells and micro-emboli substantially hindered lung metastasization. Cas9hIL30-PSCA-NPs inhibited PC cell proliferation and expression of IL30 and metastasis-drivers, such as CXCR2, CXCR4, IGF1, L1CAM, METAP2, MMP2 and TNFSF10, whereas CDH1 was up-regulated. PC-Lung and PC-BM 2-OCs revealed that Cas9hIL30-PSCA-NPs suppressed PC cell release of CXCL2/GROβ, which in vivo was associated with intra-metastatic myeloid cell infiltrates, and of DKK1, OPG and IL6, which in vitro boosted endothelial-network formation and cancer cell migration. Development of a patient-tailored nanoplatform for selective CRISPR-mediated IL30 gene deletion is a clinically valuable tool against PC progression.

PiRNA PROPER Suppresses DUSP1 Translation by Targeting N6-Methyladenosine-Mediated RNA Circularization to Promote Oncogenesis of Prostate Cancer.

Genetic and epigenetic alterations occur in many physiological and pathological processes. The existing knowledge regarding the association of PIWI-interacting RNAs (piRNAs) and their genetic variants on risk and progression of prostate cancer (PCa) is limited. In this study, three genome-wide association study datasets are combined, including 85,707 PCa cases and 166,247 controls, to uncover genetic variants in piRNAs. Functional investigations involved manipulating piRNA expression in cellular and mouse models to study its oncogenetic role in PCa. A specific genetic variant, rs17201241 is identified, associated with increased expression of PROPER (piRNA overexpressed in prostate cancer) in tumors and are located within the gene, conferring an increased risk and malignant progression of PCa. Mechanistically, PROPER coupled with YTHDF2 to recognize N6-methyladenosine (m6A) and facilitated RNA-binding protein interactions between EIF2S3 at 5'-untranslated region (UTR) and YTHDF2/YBX3 at 3'-UTR to promote DUSP1 circularization. This m6A-dependent mRNA-looping pattern enhanced DUSP1 degradation and inhibited DUSP1 translation, ultimately reducing DUSP1 expression and promoting PCa metastasis via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PROPER expression using antagoPROPER effectively suppressed xenograft growth, suggesting its potential as a therapeutic target. Thus, targeting piRNA PROPER-mediated genetic and epigenetic fine control is a promising strategy for the concurrent prevention and treatment of PCa.

Upregulation of CKS2 in immunosuppressive cells is associated with metastasis and poor prognosis in prostate cancer: a single-cell RNA-sequencing analysis.

Metastasis worsens prostate cancer (PCa) prognosis, with the immunosuppressive microenvironment playing a key role in bone metastasis. This study aimed to investigate how an immunosuppressive environment promotes PCa metastasis and worsens prognosis of patients with PCa. Candidate oncogenes were identified through analysis of the Gene Expression Omnibus (GEO) database. A prognostic model was developed for the purpose of identifying target genes. A single-cell RNA sequencing data from GEO database was used to analyze the localization of target genes in the tumor microenvironment. A pan-cancer analysis was conducted to study the cancer-causing potential of target genes across different types of tumors. Fifty-one genes were found to be differentially expressed in bone metastasis compared to non-metastatic PCa, with CKS2 identified as the most significant gene associated with poor prognosis. CKS2 was shown to be linked to an immunosuppressive microenvironment and osteoclastic bone metastases, as shown by its negative correlation with immune cell infiltration and osteoblast-related gene expression. Moreover, CKS2 was found in immunosuppressive cells and was linked to bone metastasis in PCa. It was also overexpressed in different types of tumors, making it as an oncogenic gene. This research offers a new perspective on the potential utility of CKS2 as a therapeutic target for the prevention of metastatic PCa.

Gene Signature for Predicting Metastasis in Prostate Cancer Using Primary Tumor Expression Profiles.

Metastasis is the leading cause of death in patients diagnosed with prostate cancer (PCa), underscoring the need for reliable prediction tools to forecast the risk of metastasis at an early stage. Here, we utilize the gene expression profiles of 1,000 unique primary tumors from patients with localized PCa to develop a gene signature capable of predicting metastasis. Our signature, termed Meta-Score, comprises forty-five genes that can accurately distinguish primary tumor with high propensity for metastasis across different patient cohorts. Notably, Meta-Score maintained its robust predictive performance in an internal validation cohort of comprising primary tumor samples from 239 patients. In addition to its robust predictive performance, Meta-Score demonstrates a significant association with survival, independent of Gleason score in two independent patient cohorts, underscoring its prognostic utility. Taken together, Meta-Score is a robust risk-stratification tool that can be leveraged to identify patients at high-risk of metastasis and unfavorable survival using their primary tumor gene expression profiles.