参考文献

Cancer remains one of the leading causes of mortality worldwide,leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade,CD103 + T cells have been associated with better clinical prognosis in patients with cancer. However,the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here,we show an unexpected and transient CD61 expression,which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling,improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically,the presence of CD61 + tumor-infiltrating T lymphocytes is associated with improved clinical outcomes,mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion,this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells,which potentiates a new target for immune-based cellular therapies. Subject terms: T cells,Tumour immunology,Lymphocyte activation View Publication

Cisplatin resistance poses a major challenge in the treatment of oral squamous cell carcinoma (OSCC). Deeper investigations into the mechanisms underlying this drug resistance is of great importance. Here,we used cellular assays and clinical immunohistochemistry to examine molecular pathways involved in both innate and acquired cisplatin resistance. We demonstrated that the p62-mTORC1 signaling complex plays a pivotal role,and is driven by the EGFR signaling network,specifically through the PI3K-Akt axis and the transcription factor C/EBP-β. Elevated p -mTOR expression was associated with cancer relapse and poor prognosis among oral cancer patients. Additionally,we illustrated that mTOR inhibitors enhance the cytotoxic effect of cisplatin,by employing cancer stem cell characteristics. Our work unveils fundamental mechanisms for cisplatin resistance,thereby presenting therapeutic implications for OSCC. View Publication

Prostate cancer (PCa) is one of the most prevalent cancers in men and is associated with high mortality and disability rates. β-hydroxybutyrate (BHB),a ketone body,has received increasing attention for its role in cancer. However,its role in PCa remains unclear. This study aimed to explore the mechanism and feasibility of BHB as a treatment alternative for PCa. Colony formation assay,flow cytometry,western blot assay,and transwell assays were performed to determine the effect of BHB on the proliferation and metastasis of PCa cells. Tumor sphere formation and aldehyde dehydrogenase assays were used to identify the impact of BHB or indoleacetamide-N-methyltransferase (INMT) on the stemness of PCa cells. N6-methyladenosine (m6A)–meRIP real-time reverse transcription polymerase chain reaction and dual luciferase assays were conducted to confirm INMT upregulation via the METTL3–m6A pathway. Co-IP assay was used to detect the epigenetic modification of INMT by BHB-mediated β-hydroxybutyrylation (kbhb) and screen enzymes that regulate INMT kbhb. Mouse xenograft experiments demonstrated the antitumor effects of BHB in vivo. BHB can inhibit the proliferation,migration,and invasion of PCa cells by suppressing their stemness. Mechanistically,INMT,whose expression is upregulated by the METTL3–m6A pathway,was demonstrated to be an oncogenic gene that promotes the stem-like characteristics of PCa cells. BHB can suppress the malignant phenotypes of PCa by kbhb of INMT,which in turn inhibits INMT expression. Our findings indicate a role of BHB in PCa metabolic therapy,thereby suggesting an epigenetic therapeutic strategy to target INMT in aggressive PCa. Not applicable. The online version contains supplementary material available at 10.1186/s12935-024-03277-6. View Publication

Chemoresistance is associated with tumor relapse and unfavorable prognosis. Multiple mechanisms underlying chemoresistance have been elucidated,including stemness and DNA damage repair. Here,the involvement of the WNT receptor,FZD5,in ovarian cancer (OC) chemoresistance was investigated. OC cells were analyzed using in vitro techniques including cell transfection,western blot,immunofluorescence and phalloidin staining,CCK8 assay,colony formation,flowcytometry,real-time PCR,and tumorisphere formation. Pearson correlation analysis of the expression levels of relevant genes was conducted using data from the CCLE database. Further,the behavior of OC cells in vivo was assessed by generation of a mouse xenograft model. Functional studies in OC cells showed that FZD5 contributes to epithelial phenotype maintenance,growth,stemness,HR repair,and chemoresistance. Mechanistically,FZD5 modulates the expression of ALDH1A1,a functional marker for cancer stem-like cells,in a β-catenin-dependent manner. ALDH1A1 activates Akt signaling,further upregulating RAD51 and BRCA1,to promote HR repair. Taken together,these findings demonstrate that the FZD5-ALDH1A1-Akt pathway is responsible for OC cell survival,and targeting this pathway can sensitize OC cells to DNA damage-based therapy. The online version contains supplementary material available at 10.1186/s12964-024-01585-y. View Publication

Myeloperoxidase (MPO) is found almost exclusively in granulocytes and immature myeloid cells. It plays a key role in the innate immune system,catalysing the formation of reactive oxygen species that are important in anti‐microbial action,but MPO also oxidatively transforms the topoisomerase II (TOP2) poison etoposide to chemical forms that have elevated DNA damaging properties. TOP2 poisons such as etoposide are widely used anti‐cancer drugs,but they are linked to cases of secondary acute myeloid leukaemias through a mechanism that involves DNA damage and presumably erroneous repair leading to leukaemogenic chromosome translocations. This leads to the possibility that myeloperoxidase inhibitors could reduce the rate of therapy‐related leukaemia by protecting haematopoietic cells from TOP2 poison‐mediated genotoxic damage while preserving the anti‐cancer efficacy of the treatment. We show here that myeloperoxidase inhibition reduces etoposide‐induced TOP2B‐DNA covalent complexes and resulting DNA double‐strand break formation in primary ex vivo expanded CD34 + progenitor cells and unfractionated bone marrow mononuclear cells. Since MPO inhibitors are currently being developed as anti‐inflammatory agents this raises the possibility that repurposing of these potential new drugs could provide a means of suppressing secondary acute myeloid leukaemias associated with therapies containing TOP2 poisons. View Publication

Genetic deletion of Dusp1 eliminates CSF3R-induced leukemia. Inhibition of Dusp1 induces the expression of Bim and p53 in oncogenic context,resulting in selective demise of leukemic cells. View Publication

Brain organoids derived from human pluripotent stem cells are a promising tool for studying human neurodevelopment and related disorders. Here,we generated long-term cultures of cortical brain organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch-clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABA A receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover,metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03 YEMK . Overall,cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia. Subject areas: Neuroscience,Cellular neuroscience,Stem cells research View Publication

Despite extensive research on microbiome alterations in ulcerative colitis (UC),the role of the constituent stable microbiota remains unclear. This study,employing 16S rRNA-gene sequencing,uncovers a persistent microbial imbalance in both active and quiescent UC patients compared to healthy controls. Using co-occurrence and differential abundance analysis,the study highlights microbial constituents,featuring Phocaeicola,Collinsella,Roseburia,Holdemanella,and Bacteroides,that are not affected during the course of UC. Co-cultivation experiments,utilizing commensal Escherichia coli and Phocaeicola vulgatus,were conducted with intestinal epithelial organoids derived from active UC patients and controls. These experiments reveal a tendency for a differential response in tight junction formation and maintenance in colonic epithelial cells,without inducing pathogen recognition and stress responses,offering further insights into the roles of these microorganisms in UC pathogenesis. These experiments also uncover high variation in patients’ response to the same bacteria,which indicate the need for more comprehensive,stratified analyses with an expanded sample size. This study reveals that a substantial part of the gut microbiota remains stable throughout progression of UC. Functional experiments suggest that members of core microbiota – Escherichia coli and Phocaeicola vulgatus – potentially differentially regulate the expression of tight junction gene in the colonic epithelium of UC patients and healthy individuals. The online version contains supplementary material available at 10.1186/s13099-024-00612-0. View Publication

Homology Directed Repair (HDR) enables precise genome editing,but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes,such as Non-Homologous End Joining (NHEJ). In this study,we develop a functional,pooled screening platform to identify protein-based reagents that improve HDR in human hematopoietic stem and progenitor cells (HSPCs). We leverage this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target,53BP1,identifying optimized variants that enable new intermolecular bonds and robustly increase HDR. We show that these variants specifically reduce insertion-deletion outcomes without increasing off-target editing,synergize with a DNAPK inhibitor molecule,and can be applied at manufacturing scale to increase the fraction of cells bearing repaired alleles. This screening platform can enable the discovery of future gene editing reagents that improve HDR outcomes. Subject terms: Targeted gene repair,Homologous recombination,High-throughput screening View Publication

Mutations in mexZ,encoding a negative regulator of the expression of the mexXY efflux pump genes,are frequently acquired by Pseudomonas aeruginosa at early stages of lung infection. Although traditionally related to resistance to the first-line drug tobramycin,mexZ mutations are associated with low-level aminoglycoside resistance when determined in the laboratory,suggesting that their selection during infection may not be necessarily,or only,related to tobramycin therapy. Here,we show that mexZ -mutated bacteria tend to accumulate inside the epithelial barrier of a human airway infection model,thus colonising the epithelium while being protected against diverse antibiotics. This phenotype is mediated by overexpression of lecA,a quorum sensing-controlled gene,encoding a lectin involved in P. aeruginosa tissue invasiveness. We find that lecA overexpression is caused by a disrupted equilibrium between the overproduced MexXY and another efflux pump,MexAB,which extrudes quorum sensing signals. Our results indicate that mexZ mutations affect the expression of quorum sensing-regulated pathways,thus promoting tissue invasiveness and protecting bacteria from the action of antibiotics within patients,something unnoticeable using standard laboratory tests. Subject terms: Antimicrobial resistance,Pathogens,Infection View Publication