Proteomics of immune cells from liver tumors reveals immunotherapy targets.

Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.

Preclinical Models of Neuroendocrine Prostate Cancer.

Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer-related death amongst men in the United States. Neuroendocrine prostate cancer (NEPC) can either arise de novo or emerge as a consequence of therapy. De novo NEPC is rare, with an incidence of <2% of all PCa cases. In contrast, treatment-induced NEPC is frequent with >20% of patients with metastatic castration-resistant prostate cancer (CRPC) reported to progress to neuroendocrine (NE) differentiation. The emergence of treatment-induced NEPC is linked to the increased therapeutic pressure, due to the broad application of androgen deprivation therapy (ADT) for PCa management and the development of novel more potent androgen receptor (AR) pathway inhibitors. NEPC is a high-grade tumor type characterized by aggressive phenotype and clinical behavior. Patients affected by NEPC frequently develop visceral metastases and have a poor prognosis. The molecular mechanisms underlying the development and progression of NEPC are still poorly understood. Transcriptional and epigenetic reprogramming appears to be involved in NE progression. In this review, we aim to provide a comprehensive view of the available models for NEPC detailing their strengths and limitations. Moreover, we describe novel approaches to expand the repertoire of preclinical models to better study, prevent, or reverse NEPC. The integration of multiple preclinical models along with molecular and omics approaches will provide important insights to understand disease progression and to devise novel therapeutic strategies for the management of NEPC in the near future. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Generation of organoids starting from the prostate gland of a GEMM or a human PDX Basic Protocol 2: Ex vivo tumor sphere formation.

Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease.

Lin28 RNA-binding proteins are stem-cell factors that play key roles in development. Lin28 suppresses the biogenesis of let-7 microRNAs and regulates mRNA translation. Notably, let-7 inhibits Lin28, establishing a double-negative feedback loop. The Lin28/let-7 axis resides at the interface of metabolic reprogramming and oncogenesis and is therefore a potential target for several diseases. In this study, we use compound-C1632, a drug-like Lin28 inhibitor, and show that the Lin28/let-7 axis regulates the balance between ketogenesis and lipogenesis in liver cells. Hence, Lin28 inhibition activates synthesis and secretion of ketone bodies whilst suppressing lipogenesis. This occurs at least partly via let-7-mediated inhibition of nuclear receptor co-repressor 1, which releases ketogenesis gene expression mediated by peroxisome proliferator-activated receptor-alpha. In this way, small-molecule Lin28 inhibition protects against lipid accumulation in multiple cellular and male mouse models of hepatic steatosis. Overall, this study highlights Lin28 inhibitors as candidates for the treatment of hepatic disorders of abnormal lipid deposition.

A functional SNP regulates E-cadherin expression by dynamically remodeling the 3D structure of a promoter-associated non-coding RNA transcript.

Transcription of E-cadherin, a tumor suppressor that plays critical roles in cell adhesion and the epithelial-mesenchymal transition, is regulated by a promoter-associated non-coding RNA (paRNA). The sense-oriented paRNA (S-paRNA) includes a functional C/A single nucleotide polymorphism (SNP rs16260). The A-allele leads to decreased transcriptional activity and increased prostate cancer risk. The polymorphic site is known to affect binding of a microRNA-guided Argonaute 1 (AGO1) complex and recruitment of chromatin-modifying enzymes to silence the promoter. Yet the SNP is distant from the microRNA-AGO1 binding domain in both primary sequence and secondary structure, raising the question of how regulation occurs. Here we report the 3D NMR structure of the 104-nucleotide domain of the S-paRNA that encompasses the SNP and the microRNA-binding site. We show that the A to C change alters the locally dynamic and metastable structure of the S-paRNA, revealing how the single nucleotide mutation regulates the E-cadherin promoter through its effect on the non-coding RNA structure.

Lactate Rewires Lipid Metabolism and Sustains a Metabolic-Epigenetic Axis in Prostate Cancer.

Lactate is an abundant oncometabolite in the tumor environment. In prostate cancer, cancer-associated fibroblasts (CAF) are major contributors of secreted lactate, which can be taken up by cancer cells to sustain mitochondrial metabolism. However, how lactate impacts transcriptional regulation in tumors has yet to be fully elucidated. Here, we describe a mechanism by which CAF-secreted lactate is able to increase the expression of genes involved in lipid metabolism in prostate cancer cells. This regulation enhanced intracellular lipid accumulation in lipid droplets (LD) and provided acetyl moieties for histone acetylation, establishing a regulatory loop between metabolites and epigenetic modification. Inhibition of this loop by targeting the bromodomain and extraterminal protein family of histone acetylation readers suppressed the expression of perilipin 2 (PLIN2), a crucial component of LDs, disrupting lactate-dependent lipid metabolic rewiring. Inhibition of this CAF-induced metabolic-epigenetic regulatory loop in vivo reduced growth and metastasis of prostate cancer cells, demonstrating its translational relevance as a therapeutic target in prostate cancer. Clinically, PLIN2 expression was elevated in tumors with a higher Gleason grade and in castration-resistant prostate cancer compared with primary prostate cancer. Overall, these findings show that lactate has both a metabolic and an epigenetic role in promoting prostate cancer progression. SIGNIFICANCE: This work shows that stromal-derived lactate induces accumulation of lipid droplets, stimulates epigenetic rewiring, and fosters metastatic potential in prostate cancer.

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties.

A series of novel σ1 receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ1 ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents. 1-Methylpiperidines showed particular high σ1 receptor affinity and selectivity over the σ2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ1 affinity. Molecular dynamics simulations with per-residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine-N-atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different σ1 receptor affinities. Recorded logD7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non-small cell lung cancer cells A427 to a similar extent as the σ1 antagonist haloperidol. 1-Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ1 ligands NE100 and S1RA.

Mitochondrial Plasticity Promotes Resistance to Sorafenib and Vulnerability to STAT3 Inhibition in Human Hepatocellular Carcinoma.

The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profound reprogramming of mitochondria function and marked activation of genes required for mitochondrial protein translation and biogenesis. Mitochondrial ribosomal proteins and components of translation and import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patients show similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated (pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionable target to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727, reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. These results sustain the importance of mitochondria plasticity in response to sorafenib and identify a clinically actionable strategy for improving the treatment efficacy in HCC patients.

Inflammatory metabolic profile of South African patients with prostate cancer.

BACKGROUND: Men with African ancestry are more likely to develop aggressive prostate cancer (PCa) and to die from this disease. The study of PCa in the South African population represents an opportunity for biomedical research due to the high prevalence of aggressive PCa. While inflammation is known to play a significant role in PCa progression, its association with tumor stage in populations of African descent has not been explored in detail. Identification of new metabolic biomarkers of inflammation may improve diagnosis of patients with aggressive PCa. METHODS: Plasma samples were profiled from 41 South African men with PCa using nuclear magnetic resonance (NMR) spectroscopy. A total of 41 features, including metabolites, lipid classes, total protein, and the inflammatory NMR markers, GlycA, and GlycB, were quantified from each NMR spectrum. The Bruker's B.I.-LISA protocols were used to characterize 114 parameters related to the lipoproteins. The unsupervised KODAMA method was used to stratify the patients of our cohort based on their metabolic profile. RESULTS: We found that the plasma of patients with very high risk, aggressive PCa and high level of C-reactive protein have a peculiar metabolic phenotype (metabotype) characterized by extremely high levels of GlycA and GlycB. The inflammatory processes linked to the higher level of GlycA and GlycB are characterized by a deep change of the plasma metabolome that may be used to improve the stratification of patients with PCa. We also identified a not previously known relationship between high values of VLDL and low level of GlycB in a different metabotype of patients characterized by lower-risk PCa. CONCLUSIONS: For the first time, a portrait of the metabolic changes in African men with PCa has been delineated indicating a strong association between inflammation and metabolic profiles. Our findings indicate how the metabolic profile could be used to identify those patients with high level of inflammation, characterized by aggressive PCa and short life expectancy. Integrating a metabolomic analysis as a tool for patient stratification could be important for opening the door to the development of new therapies. Further investigations are needed to understand the prevalence of an inflammatory metabotype in patients with aggressive PCa.

EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer.

The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer (Pb-Cre4 Pten flox/flox Rosa26-ERG, ERG/PTEN), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers.

Chemoenzymatic synthesis of 2,6-disubstituted tetrahydropyrans with high σ1 receptor affinity, antitumor and analgesic activity.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ1 receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g. With respect to σ1 receptor affinity and selectivity over a broad range of related (σ2, PCP binding site) and further targets, the enantiomeric benzylamines 3a and cyclohexylmethylamines 3b represent the most promising drug candidates of this series. However, the eudismic ratio for σ1 binding is only in the range of 2.5-3.3. Classical molecular dynamics (MD) simulations confirmed the same binding pose for both the tetrahydropyran 3 and cyclohexane derivatives 2 at the σ1 receptor, according to which: i) the protonated amino moiety of (2S,6R)-3a engages the same key polar interactions with Glu172 (ionic) and Phe107 (π-cation), ii) the lipophilic parts of (2S,6R)-3a are hosted in three hydrophobic regions of the σ1 receptor, and iii) the O-atom of the tetrahydropyran derivatives 3 does not show a relevant interaction with the σ1 receptor. Further in silico evidences obtained by the application of free energy perturbation and steered MD techniques fully supported the experimentally observed difference in receptor/ligand affinities. Tetrahydropyrans 3 require a lower dissociative force peak than cyclohexane analogs 2. Enantiomeric benzylamines 3a and cyclohexylmethylamines 3b were able to inhibit the growth of the androgen negative human prostate cancer cell line DU145. The cyclohexylmethylamine (2S,6R)-3b showed the highest σ1 affinity (Ki(σ1) = 0.95 nM) and the highest analgesic activity in vivo (67%).

Circulating extracellular vesicles release oncogenic miR-424 in experimental models and patients with aggressive prostate cancer.

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.

P1245 Polymorphic Variants of HSD3B1 Gene Confer Different Outcome in Specific Subgroups of Patients Infected With SARS-CoV-2.

Introduction: Severe respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the androgen receptor (AR), through ACE2 receptor and TMPRSS2, to enter nasal and upper airways epithelial cells. Genetic analyses revealed that HSD3B1 P1245C polymorphic variant increases dihydrotestosterone production and upregulation of TMPRSS2 with respect to P1245A variant, thus possibly influencing SARS-CoV-2 infection. Our aim was to characterize the HSD3B1 polymorphism status and its potential association with clinical outcomes in hospitalized patients with COVID-19 in Southern Switzerland. Materials and Methods: The cohort included 400 patients hospitalized for COVID-19 during the first wave between February and May 2020 in two different hospitals of Canton Ticino. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue blocks, and HSD3B1 gene polymorphism was evaluated by Sanger sequencing. Statistical associations were verified using different test. Results: HSD3B1 polymorphic variants were not associated with a single classical factor related to worse clinical prognosis in hospitalized patients with SARS-CoV-2. However, in specific subgroups, HSD3B1 variants played a clinical role: intensive care unit admission was more probable in patients with P1245C diabetes compared with P1245A individuals without this comorbidity and death was more associated with hypertensive P1245A>C cases than patients with P1245A diabetes without hypertension. Discussion: This is the first study showing that HSD3B1 gene status may influence the severity of SARS-CoV-2 infection. If confirmed, our results could lead to the introduction of HSD3B1 gene status analysis in patients infected with SARS-CoV-2 to predict clinical outcome.

Efficacy of Novel Bromodomain and Extraterminal Inhibitors in Combination with Chemotherapy for Castration-Resistant Prostate Cancer.

BACKGROUND: Chemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (mCRPC) nonresponsive to androgen receptor-targeted therapies. Nevertheless, the impact of chemotherapy on patient survival is limited and clinical outcome remain dismal. Bromodomain and extraterminal inhibitors (BETis) are attractive therapeutic agents and currently in clinical trials to be tested for their efficacy in prostate cancer patients. OBJECTIVE: In this study, we evaluated the activity of two clinical stage BETis, INCB054329 and INCB057643, alone and in combination with chemotherapeutics used for the treatment of mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Drug activity was evaluated in vitro by MTT, clonogenic, prostato-sphere, and flow cytometry assays. The activity in vivo was evaluated in mice bearing prostate tumor (22Rv1) xenografts. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cell growth data were analyzed to determine the maximum effect and the concentration that reduces by 50%. For concomitant treatments, the combination index was determined according to the Chou-Talalay method. For in vivo activity, changes in tumor size (T/Ci%), weight (T/Cd%), doubling time, and mouse body weight were monitored. Statistical significance was determined by one-way analysis of variance followed by a Student-Newman-Keuls or Turkey a posteriori test. RESULTS AND LIMITATIONS: INCB054329 and INCB057643 had significant activity as single agents in human prostate cancer cell lines and 22Rv1 tumor xenografts. Combined treatment with INCB057643 and any of docetaxel, olaparib, or carboplatin was synergistic/additive in vitro. Notably, INCB057643, given with a low-intensity dosing schedule, greatly enhanced the anti-tumor activity of docetaxel, carboplatin, and olaparib in 22Rv1 tumor xenografts. CONCLUSIONS: Collectively, these results provide the first evidence of the therapeutic benefit obtainable by combining BETis with non-androgen receptor-targeted therapies for the treatment of mCRPC. PATIENT SUMMARY: Chemotherapy has limited efficacy in patients with metastatic castration-resistant prostate cancer. This study provides evidence of enhanced efficacy of clinically used chemotherapeutics when given in combination with the bromodomain and extraterminal inhibitor INCB057643, expanding the horizon of the current options for the treatment of prostate cancer.

Pharmacodynamic and Pharmacokinetic Properties of Full Phosphorothioate Small Interfering RNAs for Gene Silencing In Vivo.

State-of-the-art small interfering RNA (siRNA) therapeutics such as givosiran and fitusiran are constructed from three variable components: a fully-modified RNA core that conveys metabolic stability, a targeting moiety that mediates target-cell uptake, and a linker. This structural complexity poses challenges for metabolite characterization and risk assessment after long-term patient exposure. In this study, we show that basic phosphorothioate modification of a siRNA targeting the oncoprotein Lin28B provides a useful increase in metabolic stability, without greatly compromising potency. We found that its stability in vitro matched that of nanoparticle-free patisiran in serum and surpassed it in liver tritosome extracts, although it did not reach the stability of the fitusiran siRNA core structure. Liver and kidney were the main sites of accumulation after its subcutaneous administration in mice. Despite the lack of a delivery agent-free antitumor effect, we anticipate our study to be a starting point to develop alternative siRNA scaffolds that can be degraded into naturally-occurring metabolites and help alleviate the aforementioned challenges. Furthermore, Lin28B is a promising target for cancers, and the development of such simplified siRNA analogs, possibly together with novel targeting units, holds potential.

Novel σ1 antagonists designed for tumor therapy: Structure - activity relationships of aminoethyl substituted cyclohexanes.

Depending on the substitution pattern and stereochemistry, 1,3-dioxanes 1 with an aminoethyl moiety in 4-position represent potent σ1 receptor antagonists. In order to increase the stability, a cyclohexane ring first replaced the acetalic 1, 3-dioxane ring of 1. A large set of aminoethyl substituted cyclohexane derivatives was prepared in a six-step synthesis. All enantiomers and diastereomers were separated by chiral HPLC at the stage of the primary alcohol 7, and their absolute configuration was determined by CD spectroscopy. Neither the relative nor the absolute configuration had a large impact on the σ1 affinity. The highest σ1 affinity was found for cis-configured benzylamines (1R,3S)-11 (Ki = 0.61 nM) and (1S,3R)-11 (Ki = 1.3 nM). Molecular dynamics simulations showed that binding of (1R,3S)-11 at the σ1 receptor is stabilized by the typical polar interaction of the protonated amino moiety with the carboxy group of E172 which is optimally oriented by an H-bond interaction with Y103. The lipophilic interaction of I124 with the N-substituent also contributes to the high σ1 affinity of the benzylamines. The antagonistic activity was determined in a Ca2+ influx assay in retinal ganglion cells. The enantiomeric cis-configured benzylamines (1R,3S)-11 and (1S,3R)-11 were able to inhibit the growth of DU145 cells, a highly aggressive human prostate tumor cell line. Moreover, cis-11 could also inhibit the growth of further human tumor cells expressing σ1 receptors. The experimentally determined logD7.4 value of 3.13 for (1R,3S)-11 is in a promising range regarding membrane penetration. After incubation with mouse liver microsomes and NADPH for 90 min, 43% of the parent (1R,3S)-11 remained unchanged, indicating intermediate metabolic stability. Altogether, nine metabolites including one glutathione adduct were detected by means of LC-MS analysis.

Erratum: Mapelli, S.N., et al. A Novel Prostate Cell Type-Specific Gene Signature to Interrogate Prostate Tumor Differentiation Status and Monitor Therapeutic Response (Running Title: Phenotypic Classification of Prostate Tumors). Cancers 2020, 12, 176.

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A Novel Prostate Cell Type-Specific Gene Signature to Interrogate Prostate Tumor Differentiation Status and Monitor Therapeutic Response (Running Title: Phenotypic Classification of Prostate Tumors).

In this study, we extracted prostate cell-specific gene sets (metagenes) to define the epithelial differentiation status of prostate cancers and, using a deconvolution-based strategy, interrogated thousands of primary and metastatic tumors in public gene profiling datasets. We identified a subgroup of primary prostate tumors with low luminal epithelial enrichment (LumElow). LumElow tumors were associated with higher Gleason score and mutational burden, reduced relapse-free and overall survival, and were more likely to progress to castration-resistant prostate cancer (CRPC). Using discriminant function analysis, we generate a predictive 10-gene classifier for clinical implementation. This mini-classifier predicted with high accuracy the luminal status in both primary tumors and CRPCs. Immunohistochemistry for COL4A1, a low-luminal marker, sustained the association of attenuated luminal phenotype with metastatic disease. We found also an association of LumE score with tumor phenotype in genetically engineered mouse models (GEMMs) of prostate cancer. Notably, the metagene approach led to the discovery of drugs that could revert the low luminal status in prostate cell lines and mouse models. This study describes a novel tool to dissect the intrinsic heterogeneity of prostate tumors and provide predictive information on clinical outcome and treatment response in experimental and clinical samples.

Mitochondrial fission promotes self-renewal and tumorigenic potential in prostate cancer.

The emergence of therapy-resistant cancer stem cells (CSCs) limit the efficacy of prostate cancer treatment. Using genetic knockdown and chemical inhibitors, we demonstrate the critical role of Bromodomain Containing 4 (BRD4) in promoting mitochondrial fission and sustaining CSC expansion. These findings provide a new paradigm for developing novel treatment strategies for prostate cancer.

The Prospect and Challenges to the Flow of Liquid Biopsy in Africa.

Liquid biopsy technologies have the potential to transform cancer patient management as it offers non-invasive diagnosis and real-time monitoring of disease progression and treatment responses. The use of liquid biopsy for non-invasive cancer diagnosis can have pivotal importance for the African continent where access to medical infrastructures is limited, as it eliminates the need for surgical biopsies. To apply liquid biopsy technologies in the African setting, the influence of environmental and population genetic factors must be known. In this review, we discuss the use of circulating tumor cells, cell-free nucleic acids, extracellular vesicles, protein, and other biomolecules in liquid biopsy technology for cancer management with special focus on African studies. We discussed the prospect, barriers, and other aspects that pose challenges to the use of liquid biopsy in the African continent.