Interrogating glioma-M2 macrophage interactions identifies Gal-9/Tim-3 as a viable target against PTEN -null glioblastoma

Science Advances, Journal Year: 2022, Volume and Issue: 8(27)

Published: July 8, 2022

Genomic alteration can reshape tumor microenvironment to drive malignancy. However, how PTEN deficiency influences microenvironment-mediated cell-cell interactions in glioblastoma (GBM) remains unclear. Here, we show that induces a symbiotic glioma-M2 macrophage interaction support glioma progression. Mechanistically, -deficient GBM cells secrete high levels of galectin-9 (Gal-9) via the AKT-GSK3β-IRF1 pathway. The secreted Gal-9 drives M2 polarization by activating its receptor Tim-3 and downstream pathways macrophages. These macrophages, turn, VEGFA stimulate angiogenesis growth. Furthermore, enhanced Gal-9/Tim-3 expression predicts poor outcome patients. In models, blockade signaling inhibits suppresses Moreover, α-lactose attenuates down-regulating macrophage-derived VEGFA, providing novel antivascularization strategy. Therefore, our study suggests is effective impair progression inhibiting polarization, specifically for -null GBM.

Language: Английский

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Single cell cancer epigenetics

Trends in cancer, Journal Year: 2022, Volume and Issue: 8(10), P. 820 - 838

Published: July 9, 2022

The epigenome encompasses several mechanisms controlling gene expression that can be aberrantly regulated during cancer development and progression. Tumors are highly complex heterogeneous biological systems require the study of epigenetic alterations at a single cell resolution.Several technologies developed to different layers epigenome, such as chromatin accessibility or histone modifications, have been applied in research over past few years, improving our understanding driving tumorigenesis.Although these techniques promising, most still nascent present limitations, low throughput limited coverage. In addition, analysis integration various epigenomic data modalities challenges new computational tools. Bulk sequencing methodologies allowed us make great progress research. Unfortunately, lack resolution fully unravel govern tumor heterogeneity. Consequently, many novel cell-sequencing decade, allowing explore components regulate aspects heterogeneity, namely: clonal microenvironment (TME), spatial organization, intratumoral differentiation programs, metastasis, resistance mechanisms. this review, we enable researchers epigenetics (DNA methylation, accessibility, DNA–protein interactions, 3D architecture) level, their potential applications cancer, current technical limitations. importance both basic clinical is indisputable. field important implications for disease. Indeed, non-mutational reprogramming was recently designated mechanistic determinant enables acquisition hallmark capabilities [1.Hanahan D. Hallmarks cancer: dimensions.Cancer Discov. 2022; 12: 31-46Crossref PubMed Scopus (326) Google Scholar]. Although it well established cells may arise from genetic mutations drive carcinogenesis, types strong drivers could explain malignant processes, progression [2.Turajilic S. et al.Resolving heterogeneity cancer.Nat. Rev. Genet. 2019; 20: 404-416Crossref (228) Scholar], therapy [3.Shaffer S.M. al.Rare variability drug-induced mode drug resistance.Nature. 2017; 546: 431-435Crossref (508) metastasis [4.Chen J.F. Yan Q. roles metastasis.Biochem. J. 2021; 478: 3373-3393Crossref (2) suggesting non-genetic determinants crucial role [5.Nam A.S. al.Integrating evolution by single-cell multi-omics.Nat. 22: 3-18Crossref (83) Thus, affecting non-malignant act critical evolution. These mechanisms, which genes without altering DNA sequence, fall into five main categories: (i) methylation; (ii) accessibility; (iii) modifications; (iv) interactions; (v) tridimensional architecture [6.Allis C.D. Jenuwein T. molecular hallmarks control.Nat. 2016; 17: 487-500Crossref Scholar,7.Darwiche N. Epigenetic an intimate affair.Am. Cancer Res. 2020; 10: 1954-1978PubMed Each type mechanism experimentally studied using bulk (Box 1). due cellular tumor, valuable information lost when techniques, since all possible retrieved point view masked averaging. Nonetheless, with emergence Scholar,8.Yalan L. al.Applications research: perspectives.J. Hematol. Oncol. 14: 91Crossref (15) tumoral were otherwise impossible assess now open exploration.Box 1Bulk analyze mechanismsVarious used understand mechanisms: taking advantage bisulfite chemistry, analyzed whole-genome (WGBS), reduced representation (RRBS), 450k/850k Illumina methylation arrays [128.Ortiz-Barahona V. al.Use profiling translational oncology.Semin. Biol. 83: 523-535Crossref (7) Scholar]; mainly assay transposase-accessible (ATAC-seq) [129.Marinov G.K. Shipony Z. Interrogating accessible landscape eukaryote genomes ATAC-seq.Methods Mol. 2243: 183-226Crossref (0) modifications interactions immunoprecipitation (ChIP-seq) [130.Nakato R. Sakata Methods ChIP-seq analysis: practical workflow advanced applications.Methods. 187: 44-53Crossref (6) explored multiple chromosome conformation capture technology, 3C, 4C, 5C, Hi-C, promoter-capture ChIA-PET [131.Sati Cavalli G. Chromosome impact genome function.Chromosoma. 126: 33-44Crossref (97) Scholar,132.Javierre B.M. al.Lineage-specific links enhancers non-coding disease variants target promoters.Cell. 167: 1369-1384Abstract Full Text PDF (486) One common drawback among need considerable sample size, demanding thousands millions minimal input. considered 'bulk methodologies', obtain average value whole-cell [133.Carter B. Zhao K. basis heterogeneity.Nat. 235-250Crossref (3) Various deconvolution strategies data, but substantial risk retrieving artifacts losing difficult-to-detect minor subclones [134.Chakravarthy A. al.Pan-cancer tumour composition methylation.Nat. Commun. 2018; 9: 3220Crossref (114) Nevertheless, indispensable tools its relationship cancer. For example, they methylation-based classification diffuse gliomas (LGm1-LGm6) [135.Ceccarelli M. al.Molecular reveals biologically discrete subsets pathways glioma.Cell. 164: 550-563Abstract cancers unknown primary [123.Moran al.Epigenetic classify primary: multicentre, retrospective analysis.Lancet 1386-1395Abstract (251) modification-based tracking states [136.Völker-Albert al.Histone stem implications.Stem Cell Rep. 15: 1196-1205Abstract A entity comprising cells, each has [9.Dagogo-Jack I. Shaw A.T. Tumour therapies.Nat. Clin. 81-94Crossref (1187) help properly dissect dependencies complexity. There six biology related key (Figure 1): heterogeneity; TME; organization intercellular crosstalk; developmental programs (phenotypic plasticity); metastasis; (vi) appearance therapy. necessary develop allow cues undetectable methodologies. catalog facilitate characteristics level. We technology based on under architecture), focusing first mono-omic (techniques only one cell) then multi-omic (which simultaneously cell). summarize currently available also highlight recent discoveries insights gained technologies, how contribute solve (mostly derived heterogeneity), translational/clinical scenarios. comprise subclones, unique properties [10.McGranahan Swanton C. Clonal evolution: past, present, future.Cell. 168: 613-628Abstract (1220) Scholar,11.Oakes C.C. al.Evolution linked aberrations chronic lymphocytic leukemia.Cancer 2014; 4: 348-361Crossref (113) As population evolves, accumulate clones harbor novel, selective advantages (e.g., enhanced proliferation, therapy, invasiveness, etc.) detection outcome. Single able detect (especially minor, difficult-to-detect, subclones), thus revealing prognostic information. does not solely harbors myriad distinct T content directly associated types, cytotoxic (Tc) helper (Th1, Th2, Th17) correlating good prognosis [12.Tay R.E. al.Revisiting CD4 + immunotherapy-new old paradigms.Cancer Gene Ther. 28: 5-17Crossref Tumor-associated macrophages progression, depending M1/M2 state [13.Baghban al.Tumor complexity therapeutic glance.Cell Signal. 18: 59Crossref (321) Additionally, natural killer (NK) B endothelial fibroblasts, other participate interactome [14.Anderson N.M. Simon M.C. microenvironment.Curr. 30: R921-R925Abstract (186) microenvironmental profoundly modulate nontumoral generating crosstalk determines [15.Marks D.L. control microenvironment.Epigenomics. 8: 1671-1687Crossref (32) studying signals level mandatory decipher interactome. Malignant randomly distributed inside instead occupy specific positions space, cell–cell [16.Noble al.Spatial structure governs evolution.Nat. Ecol. Evol. 6: 207-217Crossref Knowing distribution assessing 'heat' certain melanoma), relative quantity position [17.Trujillo J.A. al.T cell-inflamed versus non-T tumors: conceptual framework immunotherapy combination selection.Cancer Immunol. 990-1000Crossref (202) dependent colorectal (CRC) patients locoregional relapse-free overall survival [18.Martínez-Cardús homogeneity within tumors predicts shorter times cancer.Gastroenterology. 151: 961-972Abstract Microscopy immunohistochemistry. enabled advances aspect. specificity unveil cell. (including cutting-edge epigenomics) will infer correlate changes value. hypothesis growth depends, least part, asymmetrical divisions differentiate committed [19.Lim J.R. al.Cancer targets.Med. 38: 76Crossref background, follow program glioblastoma, there four program, some higher stemness (neural progenitor-like oligodendrocyte cells), others more differentiated (astrocyte-like mesenchymal-like cells) [20.Neftel al.An integrative model states, plasticity, genetics glioblastoma.Cell. 178: 835-849Abstract (598) identity maintained memory methylation) ensure full commitment transcriptional [21.Lee H.J. Reprogramming methylome: erasing creating diversity.Cell Stem Cell. 710-719Abstract (223) detecting machinery provide trajectories, predicting deciding treatment should applied. Some acquire ability leave site colonize distant tissues, cause cancer-related deaths [22.Fares principles metastasis: revisited.Signal Transduct. Target. 5: 28Crossref (390) From transformation until settlement tissue, metastatic experiences drastic changes, acquiring motility (epithelial–to-mesenchymal transition), avoiding immune surveillance, adapting secondary No driver yet identified, dynamic involved steps Scholar,23.Patel S.A. Vanharanta metastasis.Mol. 11: 79-96Crossref (37) useful confidently sites those metastatic-prone background. Certain abundance epimutations render them resistant treatments affect abundant [24.Wang X. al.Drug combating cancer.Cancer Drug Resist. 2: 141-160PubMed likely become predominant ones after line treatment, representing relapse. Alterations strongly antitumoral [25.Hayashi Konishi Correlation anti-tumour regulation.Br. Cancer. 124: 681-682Crossref (4) bortezomib myeloma, enter slow-cycling, drug-tolerant reversible state, consequence plasticity rather than determinants. Another case non-genetically determined H3 lysine 4 demethylases, KDM5, transcriptomic breast leading decreased sensitivity antiestrogens [26.Hinohara al.KDM5 demethylase activity resistance.Cancer 34: 939-953Abstract (96) taxane-resistant triple-negative (TNBC), global hypomethylation relocation H3K27 trimethylation paclitaxel, vulnerability inhibitors [27.Deblois switch-induced viral mimicry evasion chemotherapy-resistant 1312-1329Crossref well-documented cases [28.Marine J.-C. al.Non-genetic 743-756Crossref early diagnosis, would significantly clinicians select best combinations. residual fundamental, because constitutes biomarker predict relapse [29.Schuurhuis G.J. al.Minimal/measurable AML: consensus document European Leukemia Net MRD Working Party.Blood. 131: 1275-1291Crossref (537) encompass breakthrough methodology revolutionized way characterized looking time. approaches essential examine underlying levels. With advent RNA-sequencing (scRNA-seq), transcriptome exploited technologies. It accelerated biology, enabling characterization unprecedented Scholar,30.van Galen P. al.Single-cell RNA-seq AML hierarchies relevant immunity.Cell. 176: 1265-1281Abstract (288) Scholar, 31.Costa al.Fibroblast immunosuppressive environment human 33: 463-479Abstract (602) 32.Aoki disease-defining t-cell classic hodgkin lymphoma.Cancer 406-421Crossref (82) 33.Campillo-Marcos analyses hematopoiesis hematological malignancies.Exp. 98: 1-13Abstract emerging DNA-sequencing profile, amplicon-based targeted manner, recurrently mutated genes, providing genotype every nucleotide (SNPs) copy number (CNVs) [34.Miles L.A. mutation myeloid malignancies.Nature. 587: 477-482Crossref (117) diversity often independent highlighting developing [35.Chaligne encoding, heritability glioma states.Nat. 53: 1469-1479Crossref (20) aimed evolved rapidly compared transcriptome, being regulation. 5-Methylcytosine (5mC) well-known modification. mammals, mostly occurs cytosines followed guanine, forming 5′-to-3′ CpG pair. Approximately 70% promoters enriched clustered pairs, 'CpG islands' prone 5mC [36.Deaton A.M. Bird islands regulation transcription.Genes Dev. 2011; 25: 1010-1022Crossref (1966) regions, acts repressive switch, restricting expression. found genomic bodies regulatory regions (enhancers CTCF sites), regulating function cis. deregulated. Promoter hyper/hypomethylation suppressors/oncogenes well-established [37.Berdasco Esteller Clinical epigenetics: seizing opportunities translation.Nat. 109-127Crossref (227) deregulation enhancer fostering [38.Bell al.Enhancer dynamics patient mortality.Genome 26: 601-611Crossref (73) helped revolutionize area. Most conversion unmethylated uracil DNA. This allows methylated array-based methods al.Epi

Language: Английский

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Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 27, 2023

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated contribution GBM progression. Senescent are identified patient and mouse GBMs. Partial removal p16 Ink4a -expressing cells, which make up less than 7 % tumor, modifies ecosystem improves survival GBM-bearing female mice. By combining single cell bulk RNA sequencing, immunohistochemistry genetic knockdowns, identify NRF2 transcription factor determinant phenotype. Remarkably, our transcriptional signature underlying mechanisms senescence conserved GBMs, whom higher scores correlate with shorter times. These findings suggest that senolytic drug therapy may be beneficial adjuvant for patients GBM.

Language: Английский

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Extrachromosomal DNA amplifications in cancer

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(12), P. 760 - 771

Published: Aug. 11, 2022

Language: Английский

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Glioblastoma heterogeneity at single cell resolution

Oncogene, Journal Year: 2023, Volume and Issue: 42(27), P. 2155 - 2165

Published: June 5, 2023

Language: Английский

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Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective

Cell, Journal Year: 2024, Volume and Issue: 187(2), P. 446 - 463.e16

Published: Jan. 1, 2024

Language: Английский

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Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(12), P. 2820 - 2837

Published: Sept. 19, 2022

Abstract Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight IDH primary GBMs and defined signature (NES) tumor. show that NES significantly associates with activation transcription factors regulate brain development, including MYBL2 FOSL2. Hypoxia is involved in inducing transition potentially via HIF1A–FOSL2 axis. High-NES could recruit polarize bone marrow–derived macrophages through FOSL2–ANXA1–FPR1/3 These polarized can efficiently suppress T-cell activity accelerate cells. Moreover, upregulate CCL2 induce cell migration. Significance: GBM progression be induced hypoxia Tumor-derived ANXA1 associated recruitment polarization immunoenvironment. The promote This article highlighted In Issue feature, p. 2711

Language: Английский

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Spatial cellular architecture predicts prognosis in glioblastoma

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 11, 2023

Abstract Intra-tumoral heterogeneity and cell-state plasticity are key drivers for the therapeutic resistance of glioblastoma. Here, we investigate association between spatial cellular organization glioblastoma prognosis. Leveraging single-cell RNA-seq transcriptomics data, develop a deep learning model to predict transcriptional subtypes cells from histology images. Employing this model, phenotypically analyze 40 million tissue spots 410 patients identify consistent associations tumor architecture prognosis across two independent cohorts. Patients with poor exhibit higher proportions expressing hypoxia-induced program. Furthermore, clustering pattern astrocyte-like is associated worse prognosis, while dispersion connection astrocytes other correlate decreased risk. To validate these results, separate that utilizes images Applying data reveal survival-associated regional gene expression programs. Overall, our study presents scalable approach unravel establishes critical clinical outcomes.

Language: Английский

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Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(4), P. 974 - 1001

Published: Jan. 17, 2023

Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique immune landscape is reflected in a complex microenvironment (TIME) GBM. Here, single-cell sequencing of GBM TIME revealed that microglia were under severe oxidative stress, induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity microglia. Heterozygous Nr4a2 (Nr4a2+/-) or CX3CR1+ myeloid cell-specific (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped plasticity vivo by reducing alternatively activated and enhancing antigen presentation capacity CD8+ T cells In microglia, NR4A2 squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic inhibition attenuated protumorigenic TIME, SQLE enhanced therapeutic efficacy immune-checkpoint blockade vivo. Collectively, stress promotes growth through NR4A2-SQLE informing novel therapy paradigms cancer. Metabolic reprogramming informs synergistic vulnerabilities this immunologically cold tumor. This article highlighted Issue feature, p. 799.

Language: Английский

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DNA methylation in mammalian development and disease

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 12, 2024

The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding how this modification contributes development, ageing disease. In particular, the past decade seen many exciting mechanistic discoveries that have substantially expanded our appreciation for generic, evolutionarily ancient can be incorporated into robust epigenetic codes. Here, we summarize current distinct landscapes emerge over mammalian lifespan discuss they interact with other regulatory layers support diverse functions. We then review rising interest in alternative patterns found during senescence somatic transition cancer. Alongside advancements single-cell long-read sequencing technologies, collective insights made across these fields offer new opportunities connect biochemical genetic features cell physiology, developmental potential phenotype. Review, Smith et al. describe development within key disease states, as well different methyltransferases interface histone modifications proteins create maintain them.

Language: Английский

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