Cell Communication and Signaling最新文献

The intricate relationship between microbiota and breast cancer presents an additional risk factor that can have a profound impact on disease progression. Focusing on dysbiosis, our metagenomic analysis shows overabundance of an oral pathogenic microbe F. nucleatum and co-habitation of associated biofilm forming oral microbes in cancerous breast. Mammary gland colonization with F. nucleatum results in the development of metaplastic lesions accompanied with inflammation, DNA damage and hyper-proliferation in healthy mice. Exhibiting the impact of circulating F. nucleatum introduced via hematogenous route, breast tumor bearing mice show accelerated tumor growth and metastatic progression. Increased proliferation, migration, self-renewal and chemoresistance in breast cancer cells as well as non-tumorigenic breast epithelial cells bearing pathogenic BRCA1 mutation is observed upon F. nucleatum exposure which is internalized by the cells in a Gal-GalNAc dependent manner. Of interest, cells harboring BRCA1 mutations exhibit greater cell surface accumulation of Gal-GalNAc sugar residue. This work sheds light on the oncogenic impact of a pro-carcinogenic oral bacterium, F. nucleatum, on normal mammary epithelium and breast cancer, implicates the impairment of DNA damage and repair pathways as its functional mediators, and proposes the concept of increased vulnerability of BRCA1 mutant breast cancer cells owing to their preferential internalization of F. nucleatum.

Huntington's disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin gene resulting in an extended polyglutamine (polyQ) stretch in the protein, which is prone to aggregation and toxicity. In addition to a proteostasis imbalance, growing evidence highlights the role of mitochondrial dysfunction in HD progression. Here we explore the role of SIR-2.3/SIRT4, a mitochondrial sirtuin, in polyQ-expanded peptides and mutant huntingtin (mHTT) toxicity using C. elegans and mammalian models. Notably, loss of sir-2.3 function results in neuronal protection mediated by AMPK activation and enhanced autophagy. These neuroprotective effects require the transcription factors DAF-16/FOXO and NHR-49, which regulate autophagy and metabolism. To explore the translational potential of these findings, we used soft ATP synthase inhibitors to mimic sir-2.3 ablation, successfully reducing mHTT-induced neuronal toxicity. These results identify the SIRT4-AMPK axis as a critical regulator linking mitochondrial metabolism, autophagy, and neuronal homeostasis in HD. These findings not only advance our understanding of HD pathogenesis but also offer promising therapeutic targets for restoring proteostasis and neuronal resilience capacity against neurodegenerative diseases.

The successful progression from the zygote to the blastocyst during preimplantation development requires the coordinated execution of polarization, compaction, and lineage specification. c-Abl (Abelson Tyrosine Kinase) is a non-receptor tyrosine kinase localized in both the nucleus and cytoplasm, with the ability to shuttle between these compartments. Despite the established importance of c-Abl-mediated phosphorylation of YAP1 in the selective activation of p73, the involvement of the c-Abl/YAP/p73 signaling axis in embryonic development remains largely unexplored. Our study demonstrates that c-Abl tyrosine kinase is a key regulator of early mouse preimplantation development, controlling compaction, polarization, and lineage segregation. Using siRNA, PDGF-AA, and imatinib approaches, we showed that perturbation of c-Abl activity alters the localization and expression of pivotal transcription factors and structural proteins, including YAP, p73, TEAD4, CDX2, NANOG, E-cadherin, and PARD6. These changes collectively affect blastomere morphology, cell-cell adhesion, and epithelial organization, highlighting the multifaceted role of c-Abl in early embryogenesis. Efficient knockdown induced a 4-cell arrest, suggesting that c-Abl functions earlier than previously recognized-likely regulating blastomere polarity, cytoskeletal dynamics, and cell cycle progression. c-Abl also modulates YAP phosphorylation and TEAD4 nuclear localization, influencing trophectoderm identity in a species-specific manner. Cytoplasmic p73 localization suggests a non-apoptotic role, potentially related to organelle-associated transcriptional regulation. Furthermore, NANOG expression in the trophectoderm and reduced CDX2 levels indicate impaired lineage segregation. Collectively, these findings identify c-Abl as a critical coordinator of early mouse embryonic morphogenesis, with important implications for understanding cell fate specification and early developmental disorders.

The gut-liver-kidney axis has emerged as a central regulatory network orchestrating metabolic, immune, and inflammatory homeostasis across organ systems. At its core lies the dynamic interplay between gut microbiota and host metabolism. Dysbiosis and impaired intestinal barrier integrity facilitate the systemic translocation of microbial metabolites-such as short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine-N-oxide (TMAO), and tryptophan derivatives-which profoundly influence hepatic lipid metabolism, renal immune responses, and overall metabolic balance. This review examines the molecular mechanisms through which gut-derived metabolites contribute to liver and kidney pathology, emphasizing inter-organ signaling and the pathological cascade of the "leaky gut-hepatic injury-renal dysfunction" loop. We critically evaluate emerging therapeutic strategies targeting this axis, including probiotic supplementation, fecal microbiota transplantation (FMT), dietary modulation (low-protein, high-fiber regimens), and pharmacological detoxification (e.g., AST‑120, molecular adsorbent recirculating systems [MARS]). Finally, we propose a conceptual "diet-microbiota-drug" triad to guide precision interventions, and discuss current challenges such as interindividual variability, the lack of standardized assessment tools, and the need for integrative multi‑omics and clinical validation. A deeper mechanistic understanding of gut-organ crosstalk may pave the way for innovative therapies to restore systemic metabolic homeostasis.

Background: Resistance to anoikis, a form of programmed cell death that occurs after detachment from the surrounding extracellular matrix, is a prerequisite for the survival of circulating tumor cells (CTCs) in the bloodstream. Platelets can interact with these CTCs and protect them from cytokine- and immune cell-mediated cell death. Whether platelets can regulate anoikis resistance by controlling intrinsic gene expression changes in tumor cells that contribute to metastasis has not been studied in detail in pancreatic cancer cells.

Methods: Pancreatic cancer cells were cultured under attached or low-attachment conditions to induce and mimic anoikis. The detached cells were co-cultured with platelets and subsequent gene expression analyses were performed to identify deregulated pathways responsible for survival under detached conditions that are mediated by platelets.

Results: We observed a cell line-dependent sensitivity of pancreatic cancer cells to anoikis and that anoikis resistance was greatly enhanced by platelet interaction. RNA sequencing and transcriptome analyses identified FOXM1 as a differentially regulated gene between attached and detached cells, and its expression was modulated by platelets via an activated AKT signaling pathway. Manipulating FOXM1 protein expression via gain- and loss-of-function approaches or by inhibiting its activity using small-molecule inhibitors significantly impacts platelet-influenced death rates. Intriguingly, single-cell RNA sequencing and immunohistochemical analyses revealed higher FOXM1 expression in pancreatic cancer metastases than in primary tumors.

Conclusion: Overall, these findings suggest that targeting FOXM1 may be a promising therapeutic strategy to interfere with the metastatic progression of pancreatic cancer, which might particularly benefit patients with high blood platelet counts.

Background: The endothelium promotes a non-adherent vascular surface that facilitates tissue perfusion, prevents clotting, and limits inflammation. Endothelial cells (ECs) execute these tissue-specific functions through the integration of signaling pathways promoted by growth factors, cytokines, extracellular matrix components, and signals from mechanosensory complexes. Furthermore, ECs secrete various molecular signals, leading to the establishment of a specific niche microenvironment. Importantly, ECs can serve as sentinels against invading viral pathogens, propagating anti-viral responses such as the secretion of type I interferons (IFNs). Identification of mechanisms that alter immunity and inflammation at this critical barrier is important to understanding endothelial dysfunctions and the endothelium's overall role in disease.

Methods: To investigate the regulation and function of IFN signaling in endothelial cells, we used a conditionally immortalized human cell line. We analyzed IFN gene expression by RT-qPCR and used an Mx2 promoter-dependent bioassay to quantify the levels of secreted IFN during homeostatic conditions. Multiple cell types were screened for the ability to enhance tonic IFN production by endothelial cells in a direct coculture model. The role of direct cell-cell interactions in this behavior was studied using cell culture insert settings and inhibitors specifically targeting gap junction communication. The antiviral effects of endothelial tonic IFN production were determined with SARS-CoV-2 and HCMV infections.

Results: We demonstrate that endothelial cells can generate a type I IFN response in absence of infection under homeostatic conditions. These tonic IFN levels rise dramatically when endothelial cells are in direct contact with epithelial cells, though not when cultured with other cell types. The transcriptional induction of type I IFN genes occurs only in endothelial cells and requires direct cell-cell contacts. We further show that IFN induction can be blocked by interfering with gap junction communication and is partially dependent on the cGAS/STING pathway. Notably, the IFN activity derived by this cell type-specific interaction efficiently protects neighboring lung epithelial cells against SARS-CoV-2 infection.

Conclusions: We propose that the upregulation of tonic IFN production by the endothelial-epithelial cell axis can contribute directly to pathogen defense and/or strengthens the innate immune response by elevated priming. While the contributing molecular signaling pathways underlying this activation have not been fully identified, this newly described mechanism has potential relevance during acute or chronic lung injuries, as it enhances the level of tonic antiviral activity. Furthermore, excessive lung inflammation in nonviral pathologies may be dampened by elevated levels of tonic IFNs.

Background: Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, as tumor growth persists despite androgen receptor (AR) pathway inhibition. Glycosaminoglycans, particularly chondroitin sulfate (CS), are increasingly recognized as modulators of oncogenic signaling. However, the contribution of distinct sulfation motifs to therapeutic resistance is poorly understood. Here, we identify the CS-E motif as a critical regulator of IL-6/STAT3 signaling and a driver of hormone-independent growth in CRPC.

Methods: Transcriptomic profiling (RNA-seq), real-time PCR, and flow cytometry were employed to assess CS sulfation changes in C4-2 prostate cancer cells under androgen-deprived conditions. Because reliable tools to detect CS-E have been lacking, we engineered a novel mutant lectin (Cochlin B8) with selective affinity for CS-E. This innovation enabled precise monitoring and functional characterization of CS-E on the surface of cancer cells. Functional studies combined GALNAC4S-6ST knockdown, pharmacological inhibition with Chst15-IN-1, and signaling assays to examine effects on IL-6/STAT3 activation and cell proliferation.

Results: Androgen deprivation induced upregulation of GALNAC4S-6ST and enhanced CS-E biosynthesis on the cell surface. Elevated CS-E facilitated IL-6 binding to the cell surface, potentiated STAT3 phosphorylation, and sustained androgen-independent proliferation. Genetic or pharmacological inhibition of GALNAC4S-6ST significantly reduced CS-E levels, impaired IL-6 binding, attenuated STAT3 activation, and selectively suppressed proliferation under hormone-depleted conditions (IC₅₀ = 1.39 µM under androgen-deprived conditions vs. 4.46 µM under androgen-replete conditions). These effects were specific to IL-6/STAT3, with no detectable impact on AR-independent EGFR or WNT signaling pathways.

Conclusions: This study reveals a previously unrecognized mechanism whereby CS-E sustains CRPC progression by selectively enhancing IL-6/STAT3 signaling when AR signaling is suppressed. Importantly, the development of Cochlin B8 overcomes a major technical barrier in CS-E research, providing a novel tool for its specific detection and functional analysis. Targeting CS-E biosynthesis represents a promising therapeutic strategy to counter resistance and improve prostate cancer treatment.

Traumatic brain injury (TBI) induces profound neuroinflammation, leading to secondary brain damage and neurological dysfunction. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in amplifying inflammatory responses after injury. This study investigates the involvement of the NLRP3 inflammasome and gasdermin D (GSDMD) in regulating NET formation and subsequent microglia-mediated neuroinflammation after TBI. Using a male mouse model of TBI, we demonstrate that activation of the NLRP3/GSDMD axis significantly enhances NET release from neutrophils. These NETs further activate microglia, promoting the secretion of proinflammatory cytokines, exacerbating blood-brain barrier damage, and worsening neurological deficits. Pharmacological inhibition of NLRP3 and GSDMD markedly attenuates NET formation, reduces microglial activation, and ameliorates neuroinflammation and neurological deficits. Collectively, our findings reveal a mechanistic pathway linking NLRP3/GSDMD-dependent NET formation with microglia-driven neuroinflammation, providing potential therapeutic targets for mitigating secondary injury following TBI.

Background & aims: The Wnt/β-catenin signaling pathway is critical for liver homeostasis. We have previously shown that hepatocyte β-catenin plays a pleiotropic role in cholestatic injury. However, the role of cholangiocyte β-catenin signaling during cholestasis remains unclear.

Methods: Inducible-Osteopontin (OPN)-Cre-β-catenin-floxed C57BL/6 mice were used in two cholestasis models. Mdr2 knockout (KO)-β-catenin-floxed:OPN-Cre mice were administered tamoxifen to delete β-catenin from cholangiocytes. Wild-type and cholangiocyte β-catenin KO mice were also administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce cholestasis. Serum was collected to evaluate liver enzymes. qRT-PCR and immunohistochemistry/immunofluorescence assays were performed on whole livers to assess injury, vascular remodeling, and hepatocyte reprogramming. Livers were isolated for transmission electron microscopy. Isolated cholangiocytes were analyzed by RNA-seq. Cholangiocytes were treated with β-catenin siRNA and lipopolysaccharide in vitro to determine changes in angiogenic factors and NF-κB activation. Conditioned media from cholangiocytes were used to evaluate endothelial cell proliferation in vitro.

Results: Mice lacking cholangiocyte β-catenin showed similar levels of hepatobiliary injury compared to controls. We observed more hepatocytes expressing cholangiocyte markers and ductular cells expressing β-catenin in β-catenin KO animals, indicating enhanced hepatocyte reprogramming. Interestingly, cholangiocyte β-catenin KO also had fibrotic hepatic arteries and increased angiogenesis versus controls. Histology and transmission electron microscopy revealed increased basement membrane formation and loss of fenestrations in the sinusoids of β-catenin KO animals. RNA-seq of isolated β-catenin KO cholangiocytes revealed increased expression of angiogenesis pathways that was associated with NF-κB activation. In vitro studies silencing β-catenin in cholangiocytes induced Vegf and Pdgfb expression. Lipopolysaccharide stimulation increased NF-κB nuclear localization in β-catenin-silenced cholangiocytes. Stimulated media from these cells promoted endothelial cell proliferation, recapitulating the angiogenic phenotype found in vivo.

Conclusions: β-catenin signaling in cholangiocytes is a novel mediator of cell-cell communication, and its loss induces a pro-angiogenic phenotype and supports hepatocyte reprogramming during cholestasis, both of which may prevent accelerated liver injury.