Cell Communication and Signaling最新文献

Prostate cancer (PC) progression is predominantly driven by androgen signaling, making androgen deprivation therapy (ADT) the standard treatment. However, the transition to castration-resistant prostate cancer (CRPC) significantly reduces ADT efficacy. While taxanes such as docetaxel (Dtx) and cabazitaxel (Cbz) are widely employed, therapeutic resistance remains a major clinical obstacle. To address this, we established docetaxel-resistant CRPC models and performed an epigenetic drug screen, identifying MLL-Menin and MLL-WDR5 inhibitors as potent agents capable of restoring taxane sensitivity through G₂/M arrest and apoptosis induction. Functional depletion of Menin (MEN1) revealed its critical role in sustaining chemoresistance, selectively impairing proliferation in resistant cells, and preventing resistance emergence in parental lines.Integrative transcriptomic (RNA-seq) and epigenomic (CUT&RUN-seq) analyses suggested that Menin may play a regulatory role in mTOR signaling and E2F target pathways. Menin binding to the promoters of mTOR and Cyclin D1 was confirmed, and rescue experiments further validated its regulatory role. Analysis of TCGA datasets demonstrated co-expression of MEN1 and mTOR in advanced metastatic PC, supporting clinical relevance. Moreover, combination treatment with the mTOR inhibitor Torin-1 and docetaxel synergistically enhanced therapeutic response in Menin-depleted resistant cells. MEN1 knockdown also abrogated tumor growth in vivo.These findings identify Menin as one of the key mediator of taxane resistance in CRPC through the regulation of mTOR. Targeting Menin, alone or in combination with mTOR inhibition, represents a promising strategy to overcome resistance and improve therapeutic outcomes in taxane-refractory PC.

The spatiotemporal control of Wnt signaling orchestrates embryonic development and tissue homeostasis, while dysregulation of this pathway has been linked to a variety of diseases, including cancer, fibrosis and neurodegeneration. Although nuclear accumulation of β-catenin serves as a hallmark of Wnt pathway hyperactivation, the mechanisms controlling nuclear β-catenin remain obscure and are subjected to some conflicting hypotheses. In this narrative review, we summarize current understanding of the complex interplays fine-tunning the nucleocytoplasmic trafficking and subcellular distribution of β-catenin. We also present computational analysis to explore candidate molecules regulating nuclear β-catenin and suggest new perspectives to future study. Finally, we discuss how these insights could pave the way for mechanism-based approaches to target "undruggable" Wnt signaling for Wnt-driven diseases.

Background: Targeting CDKs has emerged as a significant strategy in cancer drug development. While CDK4/6 inhibitors have proven effective in several cancers, CDK2 and CDK9 inhibitors are under clinical trials. In biliary tract cancer (BTC), CDK2 and CDK9 expression levels are elevated compared to normal tissue. CDK9, a transcriptional CDK, regulates RNAPII, promoting the transcription of oncogenes, such as MCL1. Aberrant CDK activation contributes to cancer progression and apoptosis evasion in BTC. Notably, MCL1 is frequently amplified in intrahepatic cholangiocarcinoma (16-21%), supporting the therapeutic potential of CDK2 and CDK9. However, targeting CDK2/9 in BTC has not yet been explored. This study aimed to evaluate CDK2/9 inhibition and develop possible biomarker strategies in BTC.

Methods: Nine BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1196, SNU2670, SNU2773, TFK1, and HUCCT1) were used. Fadraciclib (CDK2/9 inhibitor), olaparib (PARP inhibitor), and JQ1 (BRD4 inhibitor) were used. Anti-cancer effects were evaluated using MTT assay, colony formation assay, annexin-V assay, and cell cycle analysis. HR-mediated DNA damage repair was assessed using foci formation assay and DRGFP assay. Combination therapies were evaluated in vitro and in vivo.

Results: Fadraciclib was more effective in MCL1-High cells, reducing RNAPII phosphorylation and MCL1. Fadraciclib also inhibited HR gene transcription. Fadraciclib-olaparib combination showed synergy in MCL1-High cells and xenograft models. Conversely, in MCL1-Low cells, Fadraciclib upregulated BRD4, restoring RNAP II activity and oncogenes transcription. Combination of fadraciclib-JQ1 suppressed this restoration and showed synergy in vitro and in vivo.

Conclusions: MCL1-High BTCs are sensitive to CDK2/9 inhibition and benefit from combination with PARP inhibitor. In MCL1-Low BTCs, combining CDK2/9 inhibitor and BRD4 inhibitor may represent an optimal strategy for new drug development.

Despite the dual roles of GALNT3 in various cellular processes in tumorigenesis of solid tumors, the clinical and biological significance of GALNT3 in lymphomagenesis remains largely unknown. Herein, our bioinformatics analysis uncovers that GALNT3 dependent glucose metabolism was significantly elevated in DLBCL. Our DLBCL cohort study revealed that GALNT3 positivity is significantly associated with worse prognosis and clinical outcomes in DLBCL pathogenesis. Biologically, GALNT3 overexpression were found to promote DLBCL cell proliferation and cell cycle progression, while silencing GALNT3 inhibited lymphomagenesis. RNA-seq uncovers that GALNT3 upregulated FGFR2-MAPK signaling pathway in DLBCL. Moreover, protein mass spectrometry identified two potential O-Glycosylation sites of FGFR2 (Thr319 and Ser299). Further point mutation of glycosylation sites, confirmed that GALNT3 O-Glycosylates FGFR2 through Thr319. Besides, in vitro and in vivo rescue experiments demonstrated that Thr319 is indispensable for GALNT3-FGFR2-MAPK induced lymphomagenesis. In vitro pharmacological inhibition of FGFR2 with a selective inhibitor Futibatinib further demonstrated that it inhibited DLBCL cell growth, cell proliferation, induced cell cycle arrest, promoted cell apoptosis. Further in vivo study found that combination of Futibatinib with chemotherapy displayed better anti-tumor activity relative to single drug therapy in DLBCL treatment. Collectively, our data highlight the importance of considering the GALNT3-FGFR2-MAPK signaling axis as an attractive therapeutic target for lymphomagenesis. Besides, in vitro and in vivo rescue experiments demonstrated that Thr319 is indispensable for GALNT3-FGFR2-MAPK induced lymphomagenesis. In vitro pharmacological inhibition of FGFR2 with a selective inhibitor Futibatinib further demonstrated that it inhibited DLBCL cell growth, cell proliferation, induced cell cycle arrest, promoted cell apoptosis. Further in vivo study found that combination of Futibatinib with chemotherapy displayed better anti-tumor activity relative to single drug therapy in DLBCL treatment.Collectively, our data highlight the importance of considering the GALNT3-FGFR2-MAPK signaling axis as an attractive therapeutic target for lymphomagenesis.

Introduction: Myeloid malignancies, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN), exhibit overlapping pathophysiology. Chronic MPNs can transform into secondary AML (sAML), which is associated with poor prognosis and limited treatment options. However, the process and prognostic significance of leukemic transformation remain incompletely understood.

Method: Through a two-sample bidirectional Mendelian randomization (MR) analysis, we showed that genetic liability to MPN significantly predicts the risk of developing AML, establishing MPN as the precursor to leukemia. To identify mediators of this risk, we integrated population-level plasma proteomics data, identifying 55 proteins associated with MPN. Upon integrative analysis with the BEAT-AML cohort, we developed a prognostic proteogenomic gene signature, showing that higher expression of CDCP1, CRISP3, and DXCR, alongside lower MPO levels, correlates with worse AML outcomes. We further performed pharmacogenomic analysis to identify vulnerability to PI3K/AKT/mTOR signaling pathway inhibition in high-risk AML. In vitro and in vivo experiments validated the efficacy of mTOR inhibition in myeloid malignancies.

Results: This gene signature effectively stratified patients by risk, with significant survival differences across the BEAT-AML and TCGA-LAML cohorts, and revealed immune alterations in high-risk groups, including elevated monocyte prevalence and cytokine signaling activity. Single-cell RNA sequencing (scRNA-seq) further suggested enrichment of these genes in progenitor cells and AML blasts. Drug sensitivity predictions suggested that high-risk AML patients may be particularly responsive to PI3K/AKT/mTOR signaling pathway inhibitors. Consistently, we observed upregulation of the genes in cell line models harboring MPN and AML mutations, which was suppressible via dual PI3K/mTOR inhibitor Omipalisib. The efficiency of PI3K/mTOR inhibition in myeloid malignancies was further corroborated by results from multiple in vivo models.

Conclusion: Together, our findings revealed shared molecular features across MPN and AML, identified a prognostic gene signature for risk stratification, and provided rationale for PI3K/mTOR inhibition as a promising therapeutic strategy in myeloid malignancies.

Zika virus (ZIKV), a neurotropic virus, poses significant global health challenges because of its ability to cause severe neurological complications and congenital brain abnormalities. Prenatal ZIKV infection impairs early brain development. However, details of the molecular mechanisms driving their virulence remain incompletely understood. Here, we performed comparatively analyses of infection outcomes caused by 2 different ZIKV strains - wild-type (WT) ZIKV versus an attenuated strain (DN-2) - in human cerebral organoids (hCOs) to dissect host responses that could contribute to pathogenicity. Although both viral strains productively infected hCOs with indiscernible gross pathological changes, differences in host responses and subtypes of cells infected discriminate WT ZIKV from DN-2 infections. Single cell RNA sequencing analyses uncovered differently expressed genes (DEGs) that were common to both virus strains, as well as DEGs that were specific to either WT ZIKV or DN-2. For common DEGs, WT ZIKV infections elicited stronger expression of key genes involved in host immune response pathways, such as IFIT2, DDX60, OAS1 and XAF1. Moreover, analyses of WT ZIKV-specific upregulated DEGs uncovered mobilisation of additional innate immune response pathways not found in DN-2. Additionally, while WT ZIKV infected a broad range of cell types in hCOs, DN-2 infections were predominantly limited to radial glial, which are neuroprogenitors essential for neurogenesis. These results highlight that differences in host immune responses and tropism distinguish neurotropic WT ZIKV and attenuated DN-2 infections, underscoring the mechanistic differences involved in pathogenicity. Our study provides further insights into mechanisms used by neurotrophic ZIKV to drive neuropathogenesis during infection of the developing brain.

Background: Age-related decline in reproductive function is a hallmark of organismal aging, yet the molecular mechanisms driving this process remain incompletely understood. The insulin/IGF-1 signaling (IIS) pathway is highly conserved and influences both lifespan and reproductive aging in Caenorhabditis elegans, where reduced IIS extends reproductive span. While prior studies have examined isolated tissues or time points, a comprehensive temporal analysis of gonadal transcriptional dynamics under reduced IIS has been lacking. Here, we compared IIS-dependent regulation of the gonadal transcriptome with that of other somatic tissues to uncover tissue-specific mechanisms of reproductive aging.

Methods: Bulk RNA sequencing was performed on distal gonads dissected above the spermatheca from wild-type N2 and daf-2(e1370) mutant animals, a well-established model of reduced IIS. Samples were collected at four physiologically relevant adult stages-Day 1 (young adult), Day 2, Day 6, and Day 10-covering early to late reproductive periods. In parallel, whole-worm RNA-seq was conducted for N2 and daf-2 at Day 1 and Day 10 to enable systemic comparisons. Differential gene expression analyses identified IIS-responsive transcripts that were either gonad-specific or non-gonadal. Expression datasets were further analyzed using self-organizing maps (SOMs) with hierarchical clustering. Gene network construction, functional enrichment, transcription factor enrichment, and conservation analyses were performed, and differential expression profiles were integrated with publicly available germline-, gamete-, and somatic tissue-enriched datasets.

Results: Temporal transcriptomic profiling revealed distinct IIS-dependent expression trajectories in gonadal versus non-gonadal datasets. SOM-based clustering resolved temporally regulated expression modules, while network and enrichment analyses uncovered a multilayered regulatory architecture within the gonad. Gonadal expression was enriched for structural, extracellular matrix, and signaling pathway genes, whereas non-gonadal data showed enrichment for stress response and longevity-associated pathways. Integration with germline-, gamete-, and somatic tissue-enriched datasets distinguished tissue-specific regulatory signatures. Importantly, IIS-regulated gonadal components included genes highly conserved with human orthologs.

Conclusion: This study provides a high-resolution temporal map of the gonadal transcriptome under reduced IIS and highlights gene modules potentially critical for reproductive maintenance. These findings offer a resource for dissecting tissue-specific aging programs and insulin-dependent regulation of reproductive health.

Background: Radiotherapy is a very common treatment method for various cancers; however, it is not effective for patients with radioresistance. Accordingly, the discovery of drugs for patients with radioresistance cancer is critical. This study used a Food and Drug Administration (FDA)-approved drug library to identify candidate drugs for the treatment of radioresistant colorectal cancer (CRC). This approach to drug development benefits from its low cost and time requirements and can lead to rapid clinical translation.

Methods: Drugs that suppress radioresistance in CRC cells were screened. Effects of candidate drugs on cell viability and the expression of epithelial-mesenchymal transition (EMT)-related factors were evaluated through using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and quantitative real-time PCR (qRT-PCR). The effects of TBZ, identified as a candidate, on radioresistant CRC cells and organoids were evaluated using MTT, qRT-PCR, western blotting, migration, and invasion assays. Factors mediating the suppressive effects of TBZ on tumorigenicity, including the roles of Snail and the p53-miR-34a-5p axis, were evaluated using chromatin immunoprecipitation (ChIP), promoter luciferase, western blotting, qRT-PCR, and dual luciferase assays. Expression of M2 markers in THP-1-derived macrophages was confirmed by qRT-PCR.

Results: TBZ, an anti-hyperkinesia drug, was identified as a candidate agent able to reduce tumorigenicity. In radioresistant CRC cells, treatment with TBZ downregulated EMT-related factors and decreased cell migratory ability and invasiveness via reductions in Snail expression through p53-induced miR-34a-5p. Cell migration and invasion assays confirmed that TBZ had greater inhibitory effects on the migration and invasiveness of radioresistant CRC cells than those of 5-FU. Furthermore, TBZ-induced miR-34a-5p reduced M2 macrophage polarization and IL-10 secretion, thereby reducing the tumorigenicity of radioresistant CRC cells. These findings were verified using samples from patients with CRC.

Conclusions: TBZ reduces tumorigenicity via the regulation of the p53-miR-34a-5p/Snail axis in radioresistant CRC cells and suppression of M2 macrophage polarization, decreasing IL-10 secretion. Our study provides insight into drug repurposing by revealing the mechanism by which TBZ, an FDA-approved drug, reduces tumorigenicity through communication between radioresistant CRC cells and macrophages.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by cartilage degradation, bone hyperplasia, and synovitis. It is a primary cause of joint pain and dysfunction globally. The increasing incidence of OA, driven by an aging population, profoundly impairs patients' quality of life while imposing a growing economic burden on societies and families. Thus, in-depth investigations into the pathogenesis of OA, along with the exploration of novel therapeutic targets and strategies, hold significant clinical implications and social value. The Notch signaling pathway, a highly conserved intercellular communication pathway, plays a pivotal regulatory role in cell proliferation, differentiation, apoptosis, and organogenesis. In recent years, a growing body of research has revealed that the Notch signaling pathway is crucial for maintaining bone and cartilage homeostasis, with its aberrant activation or inhibition being closely linked to the initiation and progression of OA. Therefore, this narrative review performed an extensive PubMed database search using keywords like "Notch", "osteoarthritis", "bone", "cartilage", "synovitis", "osteoblasts", "osteoclasts", and "chondrocytes", and reviewed all pertinent literature. It specifically focuses on the role of Notch signaling in the differentiation and function of osteoblasts, osteoclasts, and chondrocytes, shedding light on its mechanism in cartilage damage, subchondral bone dysfunction, and synovitis. It also explores evidence for targeted Notch pathway therapies in OA, aiming to illuminate the molecular mechanisms underlying OA pathogenesis and offer new theoretical insights and therapeutic targets for OA prevention and treatment. Additionally, this narrative review seeks to decipher the mechanisms underlying the context-dependent duality of Notch signaling in bone and cartilage, and provides a critical appraisal of the challenges confronting current targeted therapies.