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Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.
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Monócitos , Neoplasias , Humanos , Monócitos/metabolismo , Medula Óssea , Colesterol/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , HipóxiaRESUMO
MOTIVATION: Single-cell RNA sequencing (scRNA-seq) enables comprehensive characterization of the cell state. However, its destructive nature prohibits measuring gene expression changes during dynamic processes such as embryogenesis. Although recent studies integrating scRNA-seq with lineage tracing have provided clonal insights between progenitor and mature cells, challenges remain. Because of their experimental nature, observations are sparse, and cells observed in the early state are not the exact progenitors of cells observed at later time points. To overcome these limitations, we developed LineageVAE, a novel computational methodology that utilizes deep learning based on the property that cells sharing barcodes have identical progenitors. RESULTS: LineageVAE is a deep generative model that transforms scRNA-seq observations with identical lineage barcodes into sequential trajectories toward a common progenitor in a latent cell state space. This method enables the reconstruction of unobservable cell state transitions, historical transcriptomes, and regulatory dynamics at a single-cell resolution. Applied to hematopoiesis and reprogrammed fibroblast datasets, LineageVAE demonstrated its ability to restore backward cell state transitions and infer progenitor heterogeneity and transcription factor activity along differentiation trajectories. AVAILABILITY AND IMPLEMENTATION: The LineageVAE model was implemented in Python using the PyTorch deep learning library. The code is available on GitHub at https://github.com/LzrRacer/LineageVAE/. SUPPLEMENTARY INFORMATION: Available at Bioinformatics online.
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The complete blood cell count is one of the most frequently ordered laboratory tests, and many parameters, including red blood cell distribution width (RDW) and mean platelet volume (MPV), are available. The purpose of this study was to investigate the usefulness of the combination of RDW and MPV in patients with ST-segment elevation myocardial infarction (STEMI). Patients with STEMI who underwent primary percutaneous coronary intervention were retrospectively enrolled (n = 229). The association between RDW as well as MPV and cardiovascular events was investigated. The median age was 67 years, and males made up 85% of the sample. Median RDW was 13.6%, and median MPV was 8.2 fL. During a median follow-up period of 528 days (IQR 331.5-920.5), 41 patients died or experienced major adverse cardiac and cerebrovascular events (MACCEs). Patients with RDW ⧠13.7% had more deaths or MACCEs with marginal significance (p = 0.0799). Patients with MPV ⧠8.3 fL had significantly more deaths or MACCEs (p = 0.0283). Patients with RDW ⧠13.7% and MPV ⧠8.3 fL had significantly more deaths or MACCEs (p = 0.0185). MPV was significantly associated with death or adverse events in patients with STEMI who were treated with primary PCI. RDW had only a weak association with death or adverse events. The results of the combination of MPV and RDW were similar to those of MPV.
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Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Idoso , Eritrócitos , Feminino , Humanos , Masculino , Volume Plaquetário Médio , Prognóstico , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgiaRESUMO
BACKGROUND: It is important to establish cancer stem cell (CSC)-targeted therapies to eradicate cancer. As it is a CSC marker, we focused on Kruppel-like factor 5 (KLF5) in this study. METHODS: We searched for candidate microRNAs (miRNAs) that inhibited KLF5 expression by in silico analyses and screened them in colon cancer cell lines. RESULTS: We identified one promising miRNA, miR-4711-5p, that downregulated KLF5 expression by direct binding. This miRNA suppressed cell proliferation, migration and invasion ability, as well as stemness, including decreased stem cell marker expression, reactive oxygen species activity and sphere formation ability. MiR-4711-5p inhibited the growth of DLD-1 xenografts in nude mice with no adverse effects. We found that miR-4711-5p provoked G1 arrest, which could be attributed to direct binding of miR-4711-5p to TFDP1 (a heterodimeric partner of the E2F family). Our findings also suggested that direct binding of miR-4711-5p to MDM2 could upregulate wild-type p53, leading to strong induction of apoptosis. Finally, we found that miR-4711-5p had a potent tumour-suppressive effect compared with a putative anti-oncomiR, miR-34a, in tumour cell cultures derived from five patients with colorectal cancer. CONCLUSIONS: Our data suggest that miR-4711-5p could be a promising target for CSC therapy.
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Neoplasias do Colo/terapia , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/administração & dosagem , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Fator de Transcrição DP1/metabolismo , Animais , Ciclo Celular/genética , Proliferação de Células/fisiologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Células HT29 , Humanos , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Fator de Transcrição DP1/genéticaRESUMO
Cancer stem cells (CSC) are a subpopulation of tumor cells with properties of high tumorigenicity and drug resistance, which lead to recurrence and poor prognosis. Although a better understanding of CSC is essential for developing cancer therapies, scarcity of the CSC population has hindered such analyses. The aim of the present study was to elucidate whether the E-cadherin-Fc chimera protein (E-cad-Fc) enhances cancer stem-like properties because studies show that soluble E-cadherin stimulates human epithelial growth factor receptor (EGFR) and downstream signaling pathways that are reported to play a crucial role in CSC. For this purpose, we used ornithine decarboxylase (ODC)-degron-transduced (Degron(+)) KM12SM cells as a CSC model that retains relatively low CSC properties. Compared to cultures without E-cad-Fc treatment, we found that E-cad-Fc treatment further suppressed proteasome activity and largely enhanced cancer stem-like properties of ODC-degron-transduced KM12SM cells. These results include increased expression of stem cell markers Lgr5, Bmi-1, SOX9, CD44, and CD44v9, aldehyde dehydrogenase (ALDH), and enhancement of robust spheroid formation, and chemoresistance to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP). These effects could be attributed to activation of the EGFR pathway as identified by extensive phosphorylation of EGFR, ERK, PI3K, AKT, and mTOR. In SW480 cells, E-cad-Fc matrix induced some CSC markers such as CD44v9 and ALDH. We also found that E-cad-Fc matrix showed high efficiency of inducing mesenchymal changes in colon cancer cells. Our data suggest that the E-cad-Fc matrix may enhance CSC properties such as enhancement of chemoresistance and sphere formation.
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Neoplasias do Colo/patologia , Receptores ErbB , Fragmentos Fc das Imunoglobulinas , Células-Tronco Neoplásicas/patologia , Proteínas Recombinantes de Fusão/metabolismo , Aldeído Desidrogenase/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos , Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Ornitina Descarboxilase , Oxaliplatina/farmacologia , Complexo Repressor Polycomb 1/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fatores de Transcrição SOX9/metabolismo , Esferoides CelularesRESUMO
Total syntheses of two natural sulphoglycolipids, disulphated glycosphingolipid SB1a and the structurally related monosulphated SM1a, are described. They have common glycan sequences and ceramide moieties and are associated with human epithelial carcinomas. The syntheses featured efficient glycan assembly and the glucosyl ceramide cassette as a versatile building block. The binding of the synthetic sulphoglycolipids by the carcinoma-specific monoclonal antibody AE3 was investigated using carbohydrate microarray technology.
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Glicoesfingolipídeos/síntese química , Compostos de Enxofre/síntese química , Carcinoma/química , Ceramidas/síntese química , Ceramidas/química , Glicoesfingolipídeos/química , Humanos , Análise em Microsséries , Polissacarídeos/síntese química , Polissacarídeos/química , Compostos de Enxofre/químicaRESUMO
Analyzing colocalization of single cells with heterogeneous molecular phenotypes is essential for understanding cell-cell interactions, and cellular responses to external stimuli and their biological functions in diseases and tissues. However, existing computational methodologies identified the colocalization patterns between predefined cell populations, which can obscure the molecular signatures arising from intercellular communication. Here, we introduce DeepCOLOR, a computational framework based on a deep generative model that recovers intercellular colocalization networks with single-cell resolution by the integration of single-cell and spatial transcriptomes. Along with colocalized population detection accuracy that is superior to existing methods in simulated dataset, DeepCOLOR identified plausible cell-cell interaction candidates between colocalized single cells and segregated cell populations defined by the colocalization relationships in mouse brain tissues, human squamous cell carcinoma samples, and human lung tissues infected with SARS-CoV-2. DeepCOLOR is applicable to studying cell-cell interactions behind various spatial niches. A record of this paper's transparent peer review process is included in the supplemental information.
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Comunicação Celular , Revisão por Pares , Humanos , Animais , Camundongos , Fenótipo , SARS-CoV-2 , Análise de Célula ÚnicaRESUMO
Objective Although malignant lymphoma (ML) can occur in every organ, diagnosing cardiac involvement without cardiac manifestations is difficult. We therefore investigated the incidence of cardiac involvement in ML in our hospital and clarified the transthoracic echocardiography (TTE) findings of cardiac involvement. Methods Patients with ML referred to our hospital between January 2013 and December 2019 were retrospectively reviewed. Patients During the study period, 453 patients were identified. The mean age was 64.9 years old, and 54% of the patients were men. Results Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma, followed by follicular lymphoma. Of the 453 patients, 394 (87.0%) underwent TTE at the initial diagnosis or during the clinical course. The performance rates of TTE in DLBCL, Hodgkin lymphoma, and mantle cell lymphoma were above 90%. Cardiac involvement was detected in 6 (five with DLBCL and one with B-cell lymphoma) (1.5%) of the 394 patients who underwent TTE. The involved lesions of the heart varied, and five patients had pericardial effusion. Five patients had a preserved left ventricular ejection fraction. All patients were treated with chemotherapy, and some were treated with radiation and surgery. Conclusion Cardiac involvement was observed in six (1.5%) of the patients with ML who underwent TTE. B-cell lymphoma, especially DLBCL, is a common ML with cardiac involvement. Although five patients had pericardial effusion, the involved lesions of the heart were not uniform. TTE is a useful imaging modality to noninvasively and repeatedly evaluate the tumor characteristics, response to ML treatment, and cardiac function.
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Linfoma Difuso de Grandes Células B , Derrame Pericárdico , Masculino , Adulto , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Estudos Retrospectivos , Derrame Pericárdico/diagnóstico por imagem , Derrame Pericárdico/epidemiologia , Derrame Pericárdico/etiologia , Volume Sistólico , Função Ventricular Esquerda , Ecocardiografia/métodos , Linfoma Difuso de Grandes Células B/diagnóstico por imagemRESUMO
BACKGROUND: Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. METHODS: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. FINDINGS: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. INTERPRETATION: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. FUNDING: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.
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Neoplasias Colorretais , Midkina , Análise de Célula Única , Linfócitos T Reguladores , Microambiente Tumoral , Feminino , Humanos , Masculino , Carcinogênese/genética , Carcinogênese/imunologia , Comunicação Celular/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transcriptoma , Microambiente Tumoral/imunologia , Midkina/imunologia , Midkina/metabolismoRESUMO
A microstructured optical fiber with a new type of waveguiding mechanism is proposed. The fiber consists of a circular rod array of high index material (n=3.48) embedded in a low index background (n=1.44). The rod array exhibits guided-mode resonance (GMR) for cylindrical waves arriving from inside the array, and thus functions as a highly reflective circular wall. Through finite-difference time-domain (FDTD) simulations, we confirmed light confinement and guidance near the GMR wavelength. Basic optical characteristics such as dispersion relations, loss spectra, and mode field profiles were calculated.
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BACKGROUND: The liver architecture of vertebrates can be classified into two types, the portal triad type (having periportal bile ducts) and the non-portal triad type (having bile ducts independent of the course of portal veins). The former is typically detectable in livers of tetrapods and cartilaginous fish, and its ancestral state is found in the hagfish, an earliest diverged lineage among vertebrates. Teleosts other than osteoglossomorphs have the latter. The aim of the present study is to reveal the changes of the hepatic innervation, biliary cilia and smooth muscle distribution, and extracellular matrices along vertebrate evolution with attention to the two types of liver architectures. METHODS: The hepatic innervation, biliary cilia and smooth muscle distribution, and collagen deposition were immunohistochemically and histochemically compared among livers of various vertebrates, using anti-acetylated tubulin and anti-α-smooth muscle actin antibodies, and Sirius red staining. These were also ultrastructurally examined. RESULTS: Although the hagfish liver had periportal intrahepatic bile ducts and ductules as detected in mammalian livers, it lacked smooth muscles around bile ducts and portal veins. Extracellular matrices in their connective tissues had thick collagen fibers. Its innervation was restricted to intrahepatic bile ducts and portal veins in the hilum. In livers of other vertebrates, including teleosts, the innervation was broadly detectable, especially around bile ducts, hepatic arteries and portal veins (afferent vessels), but not around central veins (efferent vessels). The chondrichthyans ultrastructurally had smooth muscle tissue around bile ducts. Cilia distribution was confirmed in intrahepatic bile ducts of tetrapods and basal actinopterygians. Teleosts other than osteoglossomorphs lacked cilia in their intrahepatic bile ducts. CONCLUSIONS: The liver architecture of the hagfish may be unique for innervation and extracellular matrices. Hepatic innervation may not have occurred in vertebrate ancestors. Hepatic innervation in bile ducts, hepatic arteries and portal veins may have been conserved among the extant jawed vertebrates. Cilia distribution in bile ducts may have changed during evolution of actinopterygians.
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Cílios , Fígado , Animais , Distribuição Tecidual , Fígado/anatomia & histologia , Vertebrados , Matriz Extracelular , Colágeno/metabolismo , MamíferosRESUMO
The presence of some amino acid mutations in the amino acid sequence that determines a protein's structure can significantly affect that 3D structure and its biological function. However, the effects upon structural and functional changes differ for each displaced amino acid, and it is very difficult to predict these changes in advance. Although computer simulations are very effective at predicting conformational changes, they struggle to determine whether the amino acid mutation of interest induces sufficient conformational changes, unless the researcher is a specialist in molecular structure calculations. Therefore, we created a framework that efficiently utilizes molecular dynamics and persistent homology methods to identify amino acid mutations that induce structural changes. We show that this framework can be used not only to predict conformational changes produced by amino acid mutations but also to extract groups of mutations that significantly alter similar molecular interactions, by capturing the resultant protein-protein interaction changes.
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Pancreatic cancer is one of the most aggressive cancers and the seventh leading cause of cancer-associated death in the world. Radiation is performed as an adjuvant therapy as well as anti-cancer drugs. Because cancer stem-like cells (CSCs) are considered to be radioresistant and cause recurrence and metastasis, understanding their properties is required for the development of novel therapeutic strategies. To investigate the CSC properties of pancreatic cancer cells, we used a pancreatic CSC model, degron (++) cells, which have low proteasome activity. Degron (++) cells displayed radioresistance in comparison with control cells. Using Ribonucleic acid (RNA) sequencing, we successfully identified KRT13 as a candidate gene responsible for radioresistance. Knockdown of KRT13 sensitized the degron (++) cells to radiation. Furthermore, a database search revealed that KRT13 is upregulated in pancreatic cancer cell lines and that high expression of KRT13 is associated with poorer prognosis. These results indicate that a combination therapy of KRT13 knockdown and radiation could hold therapeutic promise in pancreatic cancer.
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Neoplasias Pancreáticas , Tolerância a Radiação , Humanos , Tolerância a Radiação/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/metabolismo , Pâncreas , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral , Queratina-13/metabolismo , Neoplasias PancreáticasRESUMO
Colorectal cancers (CRCs) harboring the BRAF(V600E) mutation are associated with aggressive disease and resistance to BRAF inhibitors by feedback activation of the receptor tyrosine kinase (RTK)âRASâMAPK pathway. The oncogenic MUC1-C protein promotes progression of colitis to CRC; whereas there is no known involvement of MUC1-C in BRAF(V600E) CRCs. The present work demonstrates that MUC1 expression is significantly upregulated in BRAF(V600E) vs wild-type CRCs. We show that BRAF(V600E) CRC cells are dependent on MUC1-C for proliferation and BRAF inhibitor (BRAFi) resistance. Mechanistically, MUC1-C integrates induction of MYC in driving cell cycle progression with activation of the SHP2 phosphotyrosine phosphatase, which enhances RTK-mediated RASâERK signaling. We demonstrate that targeting MUC1-C genetically and pharmacologically suppresses (i) activation of MYC, (ii) induction of the NOTCH1 stemness factor, and (iii) the capacity for self-renewal. We also show that MUC1-C associates with SHP2 and is required for SHP2 activation in driving BRAFi-induced feedback of ERK signaling. In this way, targeting MUC1-C in BRAFi-resistant BRAF(V600E) CRC tumors inhibits growth and sensitizes to BRAF inhibition. These findings demonstrate that MUC1-C is a target for the treatment of BRAF(V600E) CRCs and for reversing their resistance to BRAF inhibitors by suppressing the feedback MAPK pathway.
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Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Mucina-1/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/genética , Transdução de SinaisRESUMO
BACKGROUND: The MUC1-C protein evolved in mammals to protect barrier tissues from loss of homeostasis; however, MUC1-C promotes oncogenesis in association with chronic inflammation. Aberrant expression of MUC1-C in cancers has been linked to depletion and dysfunction of T cells in the tumor microenvironment. In contrast, there is no known involvement of MUC1-C in the regulation of natural killer (NK) cell function. METHODS: Targeting MUC1-C genetically and pharmacologically in cancer cells was performed to assess effects on intracellular and cell surface expression of the MHC class I chain-related polypeptide A (MICA) and MICB ligands. The MICA/B promoters were analyzed for H3K27 and DNA methylation. Shedding of MICA/B was determined by ELISA. MUC1-C interactions with ERp5 and RAB27A were assessed by coimmunoprecipitation and direct binding studies. Exosomes were isolated for analysis of secretion. Purified NK cells were assayed for killing of cancer cell targets. RESULTS: Our studies demonstrate that MUC1-C represses expression of the MICA and MICB ligands that activate the NK group 2D receptor. We show that the inflammatory MUC1-CâNF-κB pathway drives enhancer of zeste homolog 2-mediated and DNMT-mediated methylation of the MICA and MICB promoter regions. Targeting MUC1-C genetically and pharmacologically with the GO-203 inhibitor induced intracellular and cell surface MICA/B expression but not MICA/B cleavage. Mechanistically, MUC1-C regulates the ERp5 thiol oxidoreductase that is necessary for MICA/B protease digestion and shedding. In addition, MUC1-C interacts with the RAB27A protein, which is required for exosome formation and secretion. As a result, targeting MUC1-C markedly inhibited secretion of exosomes expressing MICA/B. In concert with these results, we show that targeting MUC1-C promotes NK cell-mediated killing. CONCLUSIONS: These findings uncover pleotropic mechanisms by which MUC1-C confers evasion of cancer cells to NK cell recognition and destruction.
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Exossomos , Mucina-1 , Neoplasias , Humanos , Exossomos/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais , Ligantes , Mucina-1/genética , Mucina-1/metabolismo , Neoplasias/patologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Microambiente TumoralRESUMO
The incidence of inflammatory bowel disease (IBD) is increasing worldwide. It is reported that TGF-ß/Smad signal pathway is inactivated in patients with Crohn's disease by overexpression of Smad 7. With expectation of multiple molecular targeting by microRNAs (miRNAs), we currently attempted to identify certain miRNAs that activate TGF-ß/Smad signal pathway and aimed to prove in vivo therapeutic efficacy in mouse model. Through Smad binding element (SBE) reporter assays, we focused on miR-497a-5p. This miRNA is common between mouse and human species and enhanced the activity of TGF-ß/Smad signal pathway, decreased Smad 7 and/or increased phosphorylated Smad 3 expression in non-tumor cell line HEK293, colorectal cancer cell line HCT116 and mouse macrophage J774a.1 cells. MiR-497a-5p also suppressed the production of inflammatory cytokines TNF-α, IL-12p40, a subunit of IL-23, and IL-6 when J774a.1 cells were stimulated by lipopolysaccharides (LPS). In a long-term therapeutic model for mouse dextran sodium sulfate (DSS)-induced colitis, systemic delivery of miR-497a-5p load on super carbonate apatite (sCA) nanoparticle as a vehicle restored epithelial structure of the colonic mucosa and suppressed bowel inflammation compared with negative control miRNA treatment. Our data suggest that sCA-miR-497a-5p may potentially have a therapeutic ability against IBD although further investigation is essential.
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An acidic tumor microenvironment plays a critical role in tumor progression. However, understanding of metabolic reprogramming of tumors in response to acidic extracellular pH has remained elusive. Using comprehensive metabolomic analyses, we demonstrated that acidic extracellular pH (pH 6.8) leads to the accumulation of N1-acetylspermidine, a protumor metabolite, through up-regulation of the expression of spermidine/spermine acetyltransferase 1 (SAT1). Inhibition of SAT1 expression suppressed the accumulation of intra- and extracellular N1-acetylspermidine at acidic pH. Conversely, overexpression of SAT1 increased intra- and extracellular N1-acetylspermidine levels, supporting the proposal that SAT1 is responsible for accumulation of N1-acetylspermidine. While inhibition of SAT1 expression only had a minor effect on cancer cell growth in vitro, SAT1 knockdown significantly decreased tumor growth in vivo, supporting a contribution of the SAT1-N1-acetylspermidine axis to protumor immunity. Immune cell profiling revealed that inhibition of SAT1 expression decreased neutrophil recruitment to the tumor, resulting in impaired angiogenesis and tumor growth. We showed that antineutrophil-neutralizing antibodies suppressed growth in control tumors to a similar extent to that seen in SAT1 knockdown tumors in vivo. Further, a SAT1 signature was found to be correlated with poor patient prognosis. Our findings demonstrate that extracellular acidity stimulates recruitment of protumor neutrophils via the SAT1-N1-acetylspermidine axis, which may represent a metabolic target for antitumor immune therapy.
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Somatic cell reprogramming using the microRNAs miR-200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene-like behavior in multiple myeloma and T cell lymphoma, decreased in tumor samples but increased in microRNA-treated normal mucosa. Immunohistochemistry identified downregulation of c-MAF as an early tumorigenesis event in CRC, with low c-MAF expression associated with poor prognosis. Of note, c-MAF expression and p53 protein levels were inversely correlated in CRC samples. c-MAF knockout led to enhanced tumor formation in azoxymethane/dextran sodium sulfate-treated mice, with activation of cancer-promoting genes. c-MAF may play a tumor-suppressive role in CRC development.
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The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level.
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Neoplasias Colorretais , Antígenos HLA-G , Humanos , Antígenos HLA-G/genética , Osteopontina , Transcriptoma/genética , Neoplasias Colorretais/patologia , Macrófagos , Microambiente TumoralRESUMO
The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.