Road of no return——loss of TP53 paves a defined evolution path from gastric preneoplasia-to-cancer

Gastric cancer(GC),the fifth-and fourth-leading causes of morbidity and mortality worldwide,still lacks effective diagnoses and treatment.Moreover,China accounts for nearly 50%of the newly diagnosed and death cases of GC globally1.Being directly exposed to external food intake,extremely acidic content,and microorganisms,such as Helicobacter pylori and Epstein-Barr virus(EBV),stomach homeostasis is easily perturbed and disrupted.Importantly,the gastric epithelium is composed of multiple cell types,including chief,parietal,pit,and stem cells.The lineages of these gastric epithelial cells are rather plastic,giving rise to a high degree of GC heterogeneity.

Decoding the intercellular communication network during tumorigenesis

Under physiological conditions,decisions about cell fate and behavior are not made by the individual cell itself,but instead strictly depend on the collective interactions of the whole cell population in the microenvironment.Thus,continuous intercellular communication influences almost all biological processes ranging from tissue/organ development,and homeostasis maintenance,to disease progression.Regarding tumorigenesis,intercellular communications between cancer cells and other cells coexist within microenvironments involving stromal cells,immune cells,and even neural cells,playing crucial roles in tumor initiation,progression,and distal metastasis.

MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

Primary immune thrombocytopenia(ITP)is an autoimmune hemorrhagic disorder in which macrophages play a critical role.Mammalian sterile-20-like kinase 4(MST4),a member of the germinal-center kinase STE20 family,has been demonstrated to be a regulator of inflammation.Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive.The expression and function of MST4 in macrophages of ITP patients and THP-1 cells,and of a macrophage-specific Mst4−/−(Mst4ΔM/ΔM)ITP mouse model were determined.Macrophage phagocytic assays,RNA sequencing(RNA-seq)analysis,immunofluorescence analysis,coimmunoprecipitation(co-IP),mass spectrometry(MS),bioinformatics analysis,and phosphoproteomics analysis were performed to reveal the underlying mechanisms.The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients,and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment.The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages.Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines,and impaired phagocytosis,which could be increased by overexpression of MST4.In a passive ITP mouse model,macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid,attenuated the expression of M1 cytokines,and promoted the predominance of FcγRIIb in splenic macrophages,which resulted in amelioration of thrombocytopenia.Downregulation of MST4 directly inhibited STAT1 phosphorylation,which is essential for M1 polarization of macrophages.Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.

Exploration of the shared gene signatures and molecular mechanisms between periodontitis and inflammatory bowel disease:evidence from transcriptome data

Background:Periodontitis disease(PD)is associated with a systemic disorder of inflammatory bowel disease(IBD).The immune response is the common feature of the two conditions,but the more precise mechanisms remain unclear.Methods:Differential expressed genes(DEGs)analysis and weighted gene co-expression network analysis(WGCNA)were performed on PD and Crohn’s disease(CD)data sets to identify crosstalk genes linking the two diseases.The proportions of infiltrating immune cells were calculated by using Single-sample Gene Set Enrichment Analysis.In addition,a data set of isolated neutrophils from the circulation was performed via WGCNA to obtain PD-related key modules.Then,single-cell gene set enrichment scores were computed for the key module and grouped neutrophils according to score order in the IBD scRNA-seq data set.Single-cell gene enrichment analysis was used to further explore the biological process of the neutrophils.Results:A total of 13 crosstalk genes(IL1B,CSF3,CXCL1,CXCL6,FPR1,FCGR3B,SELE,MMP7,PROK2,SRGN,FCN1,TDO2 and CYP24A1)were identified via DEGs analysis and WGCNA by combining PD and CD data sets.The enrichment analysis showed that these genes were involved in interleukin-10 signaling and inflammatory response.The immune infiltration analysis showed a significant difference in the proportion of neutrophils in PD and CD compared with healthy patients.Neutrophils were scored based on the expression of a periodontitis-related gene set in the scRNA-seq data set of IBD.The enrichment analysis demonstrated that inflammatory response,TNFa signaling via NF-jB and interferon-gamma response were upregulated in the high-score group,which expressed more pro-inflammatory cytokines and chemokines compared with the low-score group.Conclusions:This study reveals a previously unrecognized mechanism linking periodontitis and IBD through crosstalk genes and neutrophils,which provides a theoretical framework for future research.

Improving hard metal implant and soft tissue integration by modulating the“inflammatory-fibrous complex”response

Soft tissue integration is one major difficulty in the wide applications of metal materials in soft tissue-related areas.The inevitable inflammatory response and subsequent fibrous reaction toward the metal implant is one key response for metal implant-soft tissue integration.It is of great importance to modulate this inflammatory-fibrous response,which is mainly mediated by the multidirectional interaction between fibroblasts and macrophages.In this study,macrophages are induced to generate M1 and M2 macrophage immune microenvironments.Their cytokine profiles have been proven to have potentially multi-regulatory effects on fibroblasts.The multi-reparative effects of soft tissue cells(human gingival fibroblasts)cultured on metal material(titanium alloy disks)in M1 and M2 immune microenvironments are then dissected.Fibroblasts in the M1 immune microenvironment tend to aggravate the inflammatory response in a pro-inflammatory positive feedback loop,while M2 immune microenvironment enhances multiple functions of fibroblasts in soft tissue integration,including soft tissue regeneration,cell adhesion on materials,and contraction to immobilize soft tissue.Enlighted by the close interaction between macrophages and fibroblasts,we propose the concept of an“inflammatory-fibrous complex”to disclose possible methods of precisely and effectively modulating inflammatory and fibrous responses,thus advancing the development of metal soft tissue materials.

A YAP/TAZ-CD54 axis is required for CXCR2-CD44-tumor-specific neutrophils to suppress gastric cancer

As an important part of tumor microenvironment,neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis.Here we defined,at single-cell resolution,CD44-CxCR2-neutrophils as tumor-specific neutrophils(tsNeus)in both mouse and human gastric cancer(GC).We uncovered a Hippo regulon in neutrophils with unique YAP signature genes(e.g.,ICAM1,CD14,EGR1)distinct from those identified in epithelial and/or cancer cells.Importantly,knockout of YAP/TAz in neutrophils impaired their differentiation into CD54+tsNeus and reduced their antitumor activity,leading to accelerated GC progression.Moreover,the relative amounts of CD54+tsNeus were found to be negatively associated with GC progression and positively associated with patient survival.Interestingly,GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+tsNeus.Furthermore,pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC,with no significant inflammation-related side effects.Thus,our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus,opening a new possibility to develop neutrophil-based antitumor therapeutics.

Author Correction:MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

In this article,the details for Affiliation 1 were incorrectly given as‘Department of Hematology,Fudan University,Shanghai 200032,China’but should have been‘Department of Hematology,Zhongshan Hospital,Fudan University,Shanghai 200032,China’;the details for Affiliation 3 were incorrectly given as‘Department of Transfusion Medicine,Fudan University,Shanghai 200032,China’but should have been‘Department of Transfusion Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,China’;the details for Affiliation 4 were incorrectly given as‘Department of Laboratory Medicine,Fudan University,Shanghai 200032,China’but should have been‘Department of Laboratory Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,China’.The original article has been corrected.

Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1-mediatedMAPK signaling

Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.

Structural and biochemical studies of RIG-I antiviral signaling

Retinoic acid-inducible gene I(RIG-I)is an important pattern recognition receptor that detects viral RNA and triggers the production of type-I interferons through the downstream adaptor MAVS(also called IPS-1,CARDIF,or VISA).A series of structural studies have elaborated some of the mechanisms of dsRNA recognition and activation of RIG-I.Recent studies have proposed that K63-linked ubiquitination of,or unanchored K63-linked polyubiquitin binding to RIG-I positively regulates MAVS-mediated antiviral signaling.Conversely phos-phorylation of RIG-I appears to play an inhibitory role in controlling RIG-I antiviral signal transduction.Here we performed a combined structural and biochemical study to further define the regulatory features of RIG-I signaling.ATP and dsRNA binding triggered dimeriza-tion of RIG-I with conformational rearrangements of the tandem CARD domains.Full length RIG-I appeared to form a complex with dsRNA in a 2:2 molar ratio.Com-pared with the previously reported crystal structures of RIG-I in inactive state,our electron microscopic struc-ture of full length RIG-I in complex with blunt-ended dsRNA,for the first time,revealed an exposed active conformation of the CARD domains.Moreover,we found that purified recombinant RIG-I proteins could bind to the CARD domain of MAVS independently of dsRNA,while S8E and T170E phosphorylation-mimick-ing mutants of RIG-I were defective in binding E3 ligase TRIM25,unanchored K63-linked polyubiquitin,and MAVS regardless of dsRNA.These findings suggested that phosphorylation of RIG inhibited downstream signaling by impairing RIG-I binding with polyubiquitin and its interaction with MAVS.

Germinal center kinases in immune regulation

Germinal center kinases （GCKs） participate in a variety of signaling pathways needed to regulate cellular functions including apoptosis, cell proliferation, polarity and migration. Recent studies have shown that GCKs are participants in both adaptive and innate immune regulation. However, the differential activation and regulatory mechanisms of GCKs, as well as upstream and downstream signaling molecules, remain to be fully defined. It remains unresolved whether and how GCKs may cross-talk with existing signaling pathways. This review stresses the progresses in research of GCKs relevant to the immune system.