Lipid metabolism, amino acid metabolism, and prostate cancer: a crucial metabolic journey.

Prostate cancer (PCa) is one of the most common malignancies in males worldwide, and its development and progression involve the regulation of multiple metabolic pathways. Alterations in lipid metabolism affect the proliferation and metastatic capabilities of PCa cells. Cancer cells increase lipid synthesis and regulate fatty acid oxidation to meet their growth and energy demands. Similarly, changes occur in amino acid metabolism in PCa. Cancer cells exhibit an increased demand for specific amino acids, and they regulate amino acid transport and metabolic pathways to fulfill their proliferation and survival requirements. These changes are closely associated with disease progression and treatment response in PCa cells. Therefore, a comprehensive investigation of the metabolic characteristics of PCa is expected to offer novel insights and approaches for the early diagnosis and treatment of this disease.

Integrative Chinese-Western medicine strategy to overcome docetaxel resistance in prostate cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicines (TCMs) have emerged as a promising complementary therapy in the management of prostate cancer (PCa), particularly in addressing resistance to Docetaxel (DTX) chemotherapy. AIM OF THE REVIEW: This review aims to elucidate the mechanisms underlying the development of resistance to DTX in PCa and explore the innovative approach of integrating TCMs in PCa treatment to overcome this resistance. Key areas of investigation include alterations in microtubule proteins, androgen receptor and androgen receptor splice variant 7, ERG rearrangement, drug efflux mechanisms, cancer stem cells, centrosome clustering, upregulation of the PI3K/AKT signaling pathway, enhanced DNA damage repair capability, and the involvement of neurotrophin receptor 1/protein kinase C. MATERIALS AND METHODS: With "Prostate cancer", "Docetaxel", "Docetaxel resistance", "Natural compounds", "Traditional Chinese medicine", "Traditional Chinese medicine compound", "Medicinal plants" as the main keywords, PubMed, Web of Science and other online search engines were used for literature retrieval. RESULTS: Our findings underscore the intricate interplay of molecular alterations that collectively contribute to the resistance of PCa cells to DTX. Moreover, we highlight the potential of TCMs as a promising complementary therapy, showcasing their ability to counteract DTX resistance and enhance therapeutic efficacy. CONCLUSION: The integration of TCMs in PCa treatment emerges as an innovative approach with significant potential to overcome DTX resistance. This review not only provides insights into the mechanisms of resistance but also presents new prospects for improving the clinical outcomes of patients with PCa undergoing DTX therapy. The comprehensive understanding of these mechanisms lays the foundation for future research and the development of more effective therapeutic interventions.

NK Cell-Targeted Immunotherapies in Bladder Cancer: Beyond Checkpoint Inhibitors.

BACKGROUND: For decades, immunotherapies have been integral for the treatment and management of bladder cancer, with immune checkpoint inhibitors (ICIs) transforming patient care in recent years. However, response rates are poor to T cell-targeted ICIs such as programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies, framing a critical need for complementary immunotherapies. Promising strategies involve harnessing the activation potential of natural killer (NK) cells. They quickly exert their antitumor activity via signaling through germline-encoded activating receptors and are rapidly sensitized to new tissue microenvironments via their regulation by polymorphic HLA class I, KIR and NKG2A receptors. OBJECTIVE: In this review, we examined the roles of currently available NK-targeted antitumor treatment strategies such as engineered viral vectors, small-molecule IMiDs, NK agonist antibodies, interleukins, and chimeric antigen receptor (CAR) NK cells, and their potential for improving the efficacy of immunotherapy in the treatment of bladder cancer. METHODS: Through review of current literature, we summarized our knowledge of NK cells in solid tumors and hematologic malignancies as their roles pertain to novel immunotherapies already being applied to the treatment of bladder cancer or that offer rationale for considering as potential novel immunotherapeutic strategies. RESULTS: NK cells play a critical role in shaping the tumor microenvironment (TME) that can be exploited to improve T cell-targeted immunotherapies. CONCLUSIONS: Emerging evidence suggests that NK cells are a prime target for improving antitumor functions in immunotherapies for the treatment of bladder cancer. Further research into profiling NK cells in settings of immunotherapies for bladder cancer could help identify patients who might maximally benefit from NK cell-targeted immunotherapies and the various approaches for exploiting their antitumor properties.

Multi-omics-based analysis of high grade serous ovarian cancer subtypes reveals distinct molecular processes linked to patient prognosis.

Despite advancements in treatment, high-grade serous ovarian cancer (HGSOC) is still characterized by poor patient outcomes. To understand the molecular heterogeneity of this disease, which underlies the challenge in selecting optimal treatments for HGSOC patients, we have integrated genomic, transcriptomic, and epigenetic information to identify seven new HGSOC subtypes using a multiscale clustering method. These subtypes not only have significantly distinct overall survival, but also exhibit unique patterns of gene expression, microRNA expression, DNA methylation, and copy number alterations. As determined by our analysis, patients with similar clinical outcomes have distinct profiles of activated or repressed cellular processes, including cell cycle, epithelial-to-mesenchymal transition, immune activation, interferon response, and cilium organization. Furthermore, we performed a multiscale gene co-expression network analysis to identify subtype-specific key regulators and predicted optimal targeted therapies based on subtype-specific gene expression. In summary, this study provides new insights into the cellular heterogeneity of the HGSOC genomic, epigenetic, and transcriptomic landscapes and provides a basis for future studies into precision medicine for HGSOC patients.

Natural killer cells: unlocking new treatments for bladder cancer.

Non-muscle invasive bladder cancer, a disease with the oldest immunotherapeutic standard of care, has seen recent improvements in treatment via the application of checkpoint blocking antibodies. Unfortunately, response rates to programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) blocking antibodies remain low despite stratification by biomarkers. Sharing common biology with T cells but lacking true antigen-specificity and responding earlier to tumorigenic threats, natural killer (NK) cells present an ideal target for combination immunotherapies. NK-targeted immunotherapies under clinical investigation, including anti-NKG2A antibodies, interleukin agonists, and engineered viral vectors, hold promise in altering the immunotherapeutic landscape in bladder cancer and will be the focus of this review.

Elevated T-cell Exhaustion and Urinary Tumor DNA Levels Are Associated with Bacillus Calmette-Guérin Failure in Patients with Non-muscle-invasive Bladder Cancer.

BACKGROUND: The functional status of immune cells in the tumor microenvironment and tumor characteristics may explain bacillus Calmette-Guérin (BCG) failure in high-risk non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To characterize molecular correlates of post-BCG high-grade (HG) recurrence using multiomics analysis. DESIGN, SETTING, AND PARTICIPANTS: Patients with BCG-treated NMIBC (n = 156) were included in the study. Metachronous tumors were analyzed using RNA sequencing (n = 170) and whole-exome sequencing (n = 195). Urine samples were analyzed for immuno-oncology-related proteins (n = 190) and tumor-derived DNA (tdDNA; n = 187). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was post-BCG HG recurrence. Cox regression and Wilcoxon rank-sum, t, and Fisher's exact tests were used for analyses. RESULTS AND LIMITATIONS: BCG induced activation of the immune system regardless of clinical response; however, immunoinhibitory proteins were observed in the urine of patients with post-BCG HG recurrence (CD70, PD1, CD5). Post-BCG HG recurrence was associated with post-BCG T-cell exhaustion (p = 0.002). Pre-BCG tumors from patients with post-BCG T-cell exhaustion had high expression of genes related to cell division and immune function. A high predicted post-BCG exhaustion score for pre-BCG tumors was associated with worse post-BCG HG recurrence-free survival (HGRFS; p = 0.002). This was validated in independent cohorts. Pre-BCG class 2a and 2b tumors (UROMOL2021 scheme) were associated with worse post-BCG HGRFS (p = 0.015). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p = 0.017) and MUC4 mutations (p = 0.002). Finally, the absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p = 0.018). The retrospective design and partial overlap for analyses are study limitations. CONCLUSIONS: Post-BCG HG recurrence may be caused by T-cell exhaustion. Tumor subtype and pre-BCG tumor characteristics may identify patients at high risk of post-BCG HG recurrence. Urinary measurements have potential for real-time assessment of treatment response. PATIENT SUMMARY: A dysfunctional immune response to bacillus Calmette-Guérin (BCG) therapy may explain high-grade recurrences of bladder cancer.

NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer.

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8+ T cells. In bladder tumors, NKG2A is acquired on CD8+ T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A+ PD-1+ CD8+ T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A+ CD8+ T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E.

Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease.

To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of multi-omics profiling of four cortical areas across 364 donors with varying cognitive and neuropathological phenotypes. Our analyses revealed thousands of molecular changes and uncovered neuronal gene subnetworks as the most dysregulated in LOAD. ATP6V1A was identified as a key regulator of a top-ranked neuronal subnetwork, and its role in disease-related processes was evaluated through CRISPR-based manipulation in human induced pluripotent stem cell-derived neurons and RNAi-based knockdown in Drosophila models. Neuronal impairment and neurodegeneration caused by ATP6V1A deficit were improved by a repositioned compound, NCH-51. This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD, and the resulting network models will serve as a blueprint for developing next-generation therapeutic agents against LOAD.

Molecular tracing of prostate cancer lethality.

Prostate cancer is diagnosed mostly in men over the age of 50 years, and has favorable 5-year survival rates due to early cancer detection and availability of curative surgical management. However, progression to metastasis and emergence of therapeutic resistance are responsible for the majority of prostate cancer mortalities. Recent advancement in sequencing technologies and computational capabilities have improved the ability to organize and analyze large data, thus enabling the identification of novel biomarkers for survival, metastatic progression and patient prognosis. Large-scale sequencing studies have also uncovered genetic and epigenetic signatures associated with prostate cancer molecular subtypes, supporting the development of personalized targeted-therapies. However, the current state of mainstream prostate cancer management does not take full advantage of the personalized diagnostic and treatment modalities available. This review focuses on interrogating biomarkers of prostate cancer progression, including gene signatures that correspond to the acquisition of tumor lethality and those of predictive and prognostic value in progression to advanced disease, and suggest how we can use our knowledge of biomarkers and molecular subtypes to improve patient treatment and survival outcomes.

Gene signatures of quiescent glioblastoma cells reveal mesenchymal shift and interactions with niche microenvironment.

BACKGROUND: Glioblastoma (GBM), a highly malignant brain tumor, invariably recurs after therapy. Quiescent GBM cells represent a potential source of tumor recurrence, but little is known about their molecular underpinnings. METHODS: Patient-derived GBM cells were engineered by CRISPR/Cas9-assisted knock-in of an inducible histone2B-GFP (iH2B-GFP) reporter to track cell division history. We utilized an in vitro 3D GBM organoid approach to isolate live quiescent GBM (qGBM) cells and their proliferative counterparts (pGBM) to compare stem cell properties and therapy resistance. Gene expression programs of qGBM and pGBM cells were analyzed by RNA-Seq and NanoString platforms. FINDINGS: H2B-GFP-retaining qGBM cells exhibited comparable self-renewal capacity but higher therapy resistance relative to pGBM. Quiescent GBM cells expressed distinct gene programs that affect cell cycle control, metabolic adaptation, and extracellular matrix (ECM) interactions. Transcriptome analysis also revealed a mesenchymal shift in qGBM cells of both proneural and mesenchymal GBM subtypes. Bioinformatic analyses and functional assays in GBM organoids established hypoxia and TGFß signaling as potential niche factors that promote quiescence in GBM. Finally, network co-expression analysis of TCGA glioma patient data identified gene modules that are enriched for qGBM signatures and also associated with survival rate. INTERPRETATION: Our in vitro study in 3D GBM organoids supports the presence of a quiescent cell population that displays self-renewal capacity, high therapy resistance, and mesenchymal gene signatures. It also sheds light on how GBM cells may acquire and maintain quiescence through ECM organization and interaction with niche factors such as TGFß and hypoxia. Our findings provide a starting point for developing strategies to tackle the quiescent population of GBM. FUND: National Institutes of Health (NIH) and Deutsche Forschungsgemeinschaft (DFG).

Modulating Notch signaling to enhance neovascularization and reperfusion in diabetic mice.

Diabetes can diminish the responsiveness to angiogenic factors (e.g., VEGF) important for wound healing and the treatment of ischemic diseases, and this study investigated the hypothesis that this effect can be reversed by altering Notch signaling. Aortic endothelial cells (ECs) isolated from diabetic mice demonstrated reduced sprouting capability in vitro, but adding a Notch inhibitor (DAPT) led to cell-density and VEGF-dose dependent enhancement of proliferation, migration and sprouting, in both 2-D and 3-D cultures, as compared to VEGF alone. The in vivo effects of VEGF and DAPT were tested in the ischemic hind limbs of diabetic mice. Combining VEGF and DAPT delivery resulted in increased blood vessel density (∼150%) and improved tissue perfusion (∼160%), as compared to VEGF alone. To examine if DAPT would interfere with vessel maturation, DAPT was also delivered with a combination of VEGF and platelet derived growth factor (PDGF). DAPT and PDGF did not interfere with the effects of the other, and highly functional and mature networks of vessels could be formed with appropriate delivery. In summary, modulating Notch signaling enhances neovascularization and perfusion recovery in diabetic mice suffering from ischemia, suggesting this approach could have utility for human diabetics.

Promoting angiogenesis via manipulation of VEGF responsiveness with notch signaling.

Promoting angiogenesis via delivery of vascular endothelial growth factor (VEGF) and other angiogenic factors is both a potential therapy for cardiovascular diseases and a critical aspect for tissue regeneration. The recent demonstration that VEGF signaling is modulated by the Notch signaling pathway, however, suggests that inhibiting Notch signaling may enhance regional neovascularization, by altering the responsiveness of local endothelial cells to angiogenic stimuli. We tested this possibility with in vitro assays using human endothelial cells, as well as in a rodent hindlimb ischemia model. Treatment of cultured human endothelial cells with DAPT, a gamma secretase inhibitor, increased cell migration and sprout formation in response to VEGF stimulation with a biphasic dependence on DAPT concentration. Further, delivery of an appropriate combination of DAPT and VEGF from an injectable alginate hydrogel system into ischemic hindlimbs led to a faster recovery of blood flow than VEGF or DAPT alone; perfusion levels reached 80% of the normal level by week 4 with combined DAPT and VEGF delivery. Direct intramuscular or intraperitoneal injection of DAPT did not result in the same level of improvement, suggesting that appropriate presentation of DAPT (gel delivery) is important for its activity. DAPT delivery from the hydrogels also did not lead to any adverse side effects, in contrast to systemic introduction of DAPT. Altogether, these results suggest a new approach to promote angiogenesis by controlling Notch signaling, and may provide new options to treat patients with diseases that diminish angiogenic responsiveness.