Featured
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| Open AccessSystematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types
Single-cell sequencing has enabled detailed analyses of the tumour microenvironment (TME). Here, the authors perform an integrative analysis of the TME using single-cell and spatial transcriptomics data from over a thousand tumours across thirty cancer types, identifying interferon-enriched community states predictive of immunotherapeutic responses.
- Junho Kang
- , Jun Hyeong Lee
- & Jong-Eun Park
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Article
| Open AccessPD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression
Immune checkpoint inhibition is a successful form of immune therapy; however response rates vary widely among individual patients. Here authors show that circulating small extracellular vesicles might contribute to poor response to anti-PD-1 treatment by carrying PD-1 and CD80 which results in higher level of vesicular PD-L1 expression in the circulation at the expense of expression on tumour cell membranes, causing immunosuppression.
- Lin-Zhou Zhang
- , Jie-Gang Yang
- & Gang Chen
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| Open AccessLongitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer
Although metabolic reprogramming within the tumour microenvironment (TME) has been reported in breast cancer, whether and how this evolves during treatment remains unclear. Here, the authors use multiple ‘omic’ analyses to examine this question in patients with breast cancer undergoing neoadjuvant chemotherapy.
- Kang Wang
- , Ioannis Zerdes
- & Theodoros Foukakis
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Article
| Open AccessMitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression
The interaction between colon cancer cells and colonic epithelial cells (CECs) is critical yet not well-known. Here, the authors show that tumor extracellular vesicles mediate mitochondrial DNA transfer to CECs, initiating mitochondrial activation and RelA-induced TGFβ1 expression, leading to tumor progression.
- Bingjie Guan
- , Youdong Liu
- & Dongwang Yan
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Article
| Open AccessVC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance
In patient with glioblastoma, a major cause of resistance to chemotherapy and radiotherapy is the high degree to intratumoral heterogeneity and cell plasticity. Here, the authors demonstrate that chemoradiation induces the reprograming of glioblastoma cells into an invasive and vessel co-opting state, termed VC-Resist, capable of promoting resistance to therapy.
- Cathy Pichol-Thievend
- , Oceane Anezo
- & Giorgio Seano
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| Open AccessA vascularized breast cancer spheroid platform for the ranked evaluation of tumor microenvironment-targeted drugs by light sheet fluorescence microscopy
Assessing tumour microenvironment-targeted drug candidates remains challenging. Here, the authors develop a comprehensive screening platform that allows for monitoring, quantifying, and ranking drug-induced effects in self-organizing, vascularized tumour spheroids.
- David Ascheid
- , Magdalena Baumann
- & Erik Henke
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Article
| Open AccessMacrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer
An inflammatory-fibrotic tumor microenvironment supports metastatic disease progression in pancreatic ductal adenocarcinoma (PDAC). Here the authors show that metastasis-infiltrating macrophages influence metastasis-associated fibroblast (MAF) heterogeneity in liver metastatic PDAC, by promoting JAK/STAT signalling pathway activation in MAFs.
- Meirion Raymant
- , Yuliana Astuti
- & Michael C. Schmid
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Article
| Open AccessMicroenvironmental reorganization in brain tumors following radiotherapy and recurrence revealed by hyperplexed immunofluorescence imaging
Improved imaging techniques are required to help advance our understanding of the complex role of the tumour microenvironment (TME). Here, the authors develop a high-throughput, highly multiplexed tissue visualisation workflow and demonstrate its utility by characterising the response of the TME to radiotherapy in preclinical models of glioblastoma.
- Spencer S. Watson
- , Benoit Duc
- & Johanna A. Joyce
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Article
| Open AccessVISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.
- Thomas Thisted
- , F. Donelson Smith
- & Edward H. van der Horst
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Article
| Open AccessLoss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment
CREBBP and KMT2D mutations frequently co-occur in B cell lymphomas with unclear significance. Here the authors show that they cooperate to skew B cell fate decisions and induce a CD8-depleted immune-evasive microenvironment to facilitate lymphomagenesis.
- Jie Li
- , Christopher R. Chin
- & Ari M. Melnick
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Article
| Open AccessSpatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones
Intratumoural heterogeneity in high-grade serous ovarian carcinoma (HGSOC) remains to be explored. Here, the authors perform spatial transcriptomics and reveal a high degree of subclonal heterogeneity in HGSOC.
- Elena Denisenko
- , Leanne de Kock
- & Alistair R. R. Forrest
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Article
| Open AccessObesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk
Obesity represents a risk factor for cancer and compromises immune function, however the mechanisms linking the two together are not fully known. Here authors show in a mouse sarcoma model that obesity increases tumour incidence, impairs intra-tumoral T cell immunity but paradoxically increases sensitivity to immune therapy via impairing immunoediting.
- Alexander Piening
- , Emily Ebert
- & Ryan M. Teague
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Article
| Open AccessDeciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
The heterogeneity of cancer associated fibroblasts (CAFs) in breast cancer has been previously described. Here the authors provide further insights into the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
- Hugo Croizer
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessSpiDe-Sr: blind super-resolution network for precise cell segmentation and clustering in spatial proteomics imaging
Imaging mass cytometry (IMC) is a powerful single-cell resolution platform for targeted spatial proteomics, but it can be constrained by imaging noise and resolution. Here, the authors propose SpiDe-Sr, a super-resolution network embedded with a denoising module for IMC spatial resolution enhancement.
- Rui Chen
- , Jiasu Xu
- & Xianting Ding
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Article
| Open AccessCancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma
Distinct genetic mutations can shape the tumor immune microenvironment. Here the authors generate preclinical mouse models of hepatocellular carcinoma bearing clinically-relevant oncogenic driver combinations, identifying myeloid cell-centric exploitable therapeutic vulnerabilities.
- Christel F. A. Ramirez
- , Daniel Taranto
- & Leila Akkari
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Article
| Open AccessSpatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Spatial positioning of cells within the tumour microenvironment may have a function in the success of immune checkpoint immunotherapy (ICI). Here the authors analyse spatial relationships from immunohistochemistry samples prior to ICI therapy and show that CD8 T cell or macrophage proximity to cancer cells is associated with better responses.
- Alberto Gil-Jimenez
- , Nick van Dijk
- & Lodewyk F. A. Wessels
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| Open AccessMetabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas
Cancer associated fibroblasts can shape the tumor microenvironment (TME) and modulate immune infiltration. Here the authors characterize the TME in preclinical models of softtissue sarcomas, identifying a subset of “glycolytic” cancer-associated fibroblasts that inhibit cytotoxic T cell infiltration into the tumor parenchyma.
- Marina T. Broz
- , Emily Y. Ko
- & Jlenia Guarnerio
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Article
| Open AccessThe bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease
Here, the authors develop a hybrid agent-based model to quantify the contributions of intrinsic cellular mechanisms and bone ecosystem factors to therapy resistance in multiple myeloma. They show that intrinsic mechanisms are essential for resistance, and that the bone microenvironment provides a protective niche that increases the likelihood.
- Ryan T. Bishop
- , Anna K. Miller
- & David Basanta
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Article
| Open AccessSpatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma
Macrophages are abundant in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Here, the authors use spatial transcriptomics to characterize macrophages in DLBCL and reactive lymphoid tissues, and propose six spatially-derived macrophage signatures that are associated with features like cell of origin and clinical outcomes.
- Min Liu
- , Giorgio Bertolazzi
- & Anand D. Jeyasekharan
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Article
| Open AccessLactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression
Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.
- Fatima Khan
- , Yiyun Lin
- & Peiwen Chen
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Article
| Open AccessDomain generalization enables general cancer cell annotation in single-cell and spatial transcriptomics
Efficient and accurate annotation of malignant cells is crucial for single-cell and spatial transcriptomics in cancer. Here, the authors develop Cancer-Finder, a deep-learning algorithm that can identify malignant cells in cancer single-cell and spatial transcriptomics data with speed and precision.
- Zhixing Zhong
- , Junchen Hou
- & Jia Song
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| Open AccessThe ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment
The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.
- Elizabeth L. Hardaker
- , Emilio Sanseviero
- & Simon T. Barry
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Article
| Open AccessExosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma
The behavior of exosomes in vivo is not completely elucidated. Here the authors develop a genetically engineered mouse model (ExoBow) to trace the distribution of exosomes, showing local and inter-organ communication networks, either specific or shared between healthy pancreas and pancreatic ductal adenocarcinoma.
- Bárbara Adem
- , Nuno Bastos
- & Sonia A. Melo
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Article
| Open AccessProteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma
The molecular characterisation of soft tissue sarcomas (STSs) across diverse populations remains crucial. Here, the authors perform a proteomics and phosphoproteomics analysis of 272 Chinese STS patients across 12 subtypes, and obtain insights related to progression, metastasis, and immune signatures.
- Shaoshuai Tang
- , Yunzhi Wang
- & Chen Ding
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Article
| Open AccessResidual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway
An important contribution of cancer associated fibroblasts (CAFs) in regulating chemoresistance has been reported. Here the authors investigate the impact of chemotherapy on CAF subsets in patients with high-grade serous ovarian cancer, suggesting that residual ANTXR1+ myofibroblasts are associated with inhibition of anti-tumor immunity.
- Monika Licaj
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessIntercellular transfer of cancer cell invasiveness via endosome-mediated protease shedding
The matrix metalloprotease MT1-MMP drives cancer metastasis. Here, the authors demonstrate how invasive cancer cells instigate non-invasive neighbouring cells to become degradative and invasive by transferring catalytically active MT1-MMP fragments.
- Eva Maria Wenzel
- , Nina Marie Pedersen
- & Camilla Raiborg
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Article
| Open AccessUPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment
Characterising the tumour microenvironment features of lung adenocarcinoma (LUAD) remains crucial. Here, the authors perform single cell RNA sequencing data analysis of 117 LUAD samples and functional assays and highlight the immunosuppressive role of UPP1high tumour cells.
- Yin Li
- , Manling Jiang
- & Chunlai Lu
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Article
| Open AccessAssessment of human leukocyte antigen-based neoantigen presentation to determine pan-cancer response to immunotherapy
HLA-I plays a key role in triggering an immune response and predicting immune checkpoint efficacy. Here the authors develop a method for quantifying HLA-I neoantigen presentation capacity by integrating HLA-I allele divergence and neoantigens numbers, termed HAPS, to describe how immune checkpoint response may be mediated by HLA.
- Jiefei Han
- , Yiting Dong
- & Zhijie Wang
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Article
| Open AccessANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation
The transcriptional program controlling the activation of cancer-associated fibroblasts (CAFs) remains to be elucidated. Here, the authors identify ANKRD1 as a mesenchymal-specific driver of CAF activation under negative direct control of androgen receptor, triggering AP-1 transcription factor complex activation.
- Luigi Mazzeo
- , Soumitra Ghosh
- & G. Paolo Dotto
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Article
| Open AccessNeutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages
Ceramide, a central molecule in sphingolipid metabolism, has been shown to affect the development and functionality of myeloid cells. Here the authors report that myeloid deficiency of neutral ceramidase (NcDase), the enzyme converting ceramide into sphingosine, induces an immunosuppressive phenotype of tumor associated macrophages, linked to T cell exhaustion in breast cancer preclinical models.
- Rui Sun
- , Chao Lei
- & Zhongbin Deng
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Article
| Open AccessRapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity
Natural killer (NK) cells control tumor growth through direct cytotoxicity and recruitment of other leukocytes. Here, using photoconversion-based labeling to track the fate of NK cells in vivo, the authors demonstrate that loss of NK cell function occurs very rapidly following their entry into tumors, but can be reversed by IL-15 administration.
- Isaac Dean
- , Colin Y. C. Lee
- & David R. Withers
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Article
| Open AccessA telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer
Therapeutic options for small cell lung cancer (SCLC) are limited. Here the authors show that a telomere-targeting drug, 6-Thio-2’-deoxyguanosine, inhibits growth of SCLC tumors by inducing telomere dysfunction preferentially in cancer initiating cells and promoting anti-tumor immune responses.
- Buse Eglenen-Polat
- , Ryan R. Kowash
- & Esra A. Akbay
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| Open AccessMacro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma
The role of the tumor microenvironment in immunotherapy response in intrahepatic cholangiocarcinoma remains unclear. Here, single cell RNA and TCR sequencing of samples before and after immunotherapy highlights the role of CD8 T-cell status conversion and exhaustion induced by Macro CD5L+ in treatment response.
- Jia-Cheng Lu
- , Lei-Lei Wu
- & Jia Fan
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Article
| Open AccessThe CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells
CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.
- Xiaofeng Liao
- , Wenxue Li
- & Dianqing Wu
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Article
| Open AccessMutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death
Oncogenic KRAS mutations can dictate the formation of an immune-suppressive tumor microenvironment. Here the authors report that, in KRAS mutant colorectal cancer, the upregulation of circATXN7 in tumor-specific cytotoxic T lymphocytes is associated with increased sensitivity to activation-induced cell death and resistance to immunotherapy.”
- Chi Zhou
- , Wenxin Li
- & Huashan Liu
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Article
| Open AccessDistinct mesenchymal cell states mediate prostate cancer progression
The components of the tumour microenvironment contribute to prostate cancer initiation and progression. Here the authors perform single-cell RNA sequencing and spatial transcriptomics analysis of prostate cancer stroma from mouse models at different stages of the disease and develop a gene signature to predict distant metastasis in patients.
- Hubert Pakula
- , Mohamed Omar
- & Massimo Loda
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Article
| Open AccessTargeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia
Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) represents a high-risk B-ALL subtype. Here the authors report that Th17 cells and IL-17A expression are elevated in Ph+ B-ALL patients and that targeting IL-17A enhances imatinib efficacy in preclinical models.
- Feng Wang
- , Yunxuan Li
- & Bing Cui
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Article
| Open AccessMAPS: pathologist-level cell type annotation from tissue images through machine learning
Current cell annotation methods using high-plex spatial proteomics data are resource intensive and demand iterative expert input. Here, the authors present MAPS (Machine learning for Analysis of Proteomics in Spatial biology), an approach that facilitates rapid and precise cell type identification with human-level accuracy from spatial proteomics data.
- Muhammad Shaban
- , Yunhao Bai
- & Faisal Mahmood
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Article
| Open AccessFOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity
Modulation of regulatory T cells (Treg) in the tumour environment is a potential avenue to bolster anti-tumor immunity. Here Liu et al show that perturbation of the negative feedback loop involving STAT1- IFITM3 influences anti-tumor immunity, and that IFITM3 or STAT1 deficiency resulting in the fragility of tumor-infiltrating Treg cells.
- Xinnan Liu
- , Weiqi Zhang
- & Bin Li
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Article
| Open AccessSingle-cell multi-omics analysis of human testicular germ cell tumor reveals its molecular features and microenvironment
The molecular features and tumour microenvironment (TME) in seminoma remain to be characterised. Here, the authors perform single cell multi-omics and spatial transcriptomics and identify key gene expression programmes, immune cell subtypes and potential therapeutic targets.
- Xiaojian Lu
- , Yanwei Luo
- & Jingtao Guo
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Article
| Open AccessPathway centric analysis for single-cell RNA-seq and spatial transcriptomics data with GSDensity
Clustering-based analysis has limited power in highly dynamic single-cell data, which is a common situation in tumour samples. Here, authors introduce GSDensity, enabling pathway-centric analysis for the direct integration of data with their domain knowledge.
- Qingnan Liang
- , Yuefan Huang
- & Ken Chen
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Article
| Open AccessSingle-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology
The authors developed a framework for joint protein-metabolite profiling at the single-cell level in human tissue combining targeted multiplexed protein imaging and untargeted spatial metabolomics in a single pipeline.
- Thomas Hu
- , Mayar Allam
- & Ahmet F. Coskun
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Article
| Open AccessDeep learning of cell spatial organizations identifies clinically relevant insights in tissue images
Cell spatial organization in tissue provides essential insights into diseases. Here, the authors show Ceograph, a graph convolutional network, for the analysis of pathology images to predict patient outcomes, highlighting cellular markers to guide personalized treatments and enhance biological understanding.
- Shidan Wang
- , Ruichen Rong
- & Guanghua Xiao
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Article
| Open AccessDelineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses
Acral melanoma (AM) is a rare melanoma subtype with unique features, where lymph node metastasis is closely associated with clinical outcomes. Here, the authors use single-cell and spatial transcriptomics to analyse early dissemination, tumour microenvironment, and heterogeneity in AM, and infer metabolic shifts with therapeutic implications.
- Chuanyuan Wei
- , Wei Sun
- & Jianying Gu
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Article
| Open AccessInhibiting stromal Class I HDACs curbs pancreatic cancer progression
The desmoplastic stroma constitutes part of the microenvironment in pancreatic ductal adenocarcinoma. Here the authors show that Class I HDACs regulate the pro-desmoplastic and pro-tumorigenic transcriptional programs to support stromal activation and tumour progression.
- Gaoyang Liang
- , Tae Gyu Oh
- & Ronald M. Evans
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Article
| Open AccessSecretory GFP reconstitution labeling of neighboring cells interrogates cell–cell interactions in metastatic niches
Methodologies to study the mechanisms of cell–cell interactions in metastatic niches remain scarce. Here, the authors develop a secretory GFP reconstitution-based system to tag tissue-resident cells neighboring on cancer cells within the metastatic niche.
- Misa Minegishi
- , Takahiro Kuchimaru
- & Satoshi Nishimura
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Article
| Open AccessMapping and modeling human colorectal carcinoma interactions with the tumor microenvironment
Tumour-microenvironment interactions, pivotal in cancer progression, are challenging to replicate in vitro. Here, the authors use single-cell RNA-seq to analyse these interactions in colorectal cancer within organoid models, and aim to emulate and understand these crucial interactions by introducing specific microenvironmental components.
- Ning Li
- , Qin Zhu
- & Christopher J. Lengner
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Article
| Open AccessFragment-sequencing unveils local tissue microenvironments at single-cell resolution
Experimentally preserving tissue microenvironments remains challenging for single-cell sequencing methods. Here, the authors introduce fragment-sequencing, a method that can preserve three-dimensional microenvironments in single-cell RNA-seq, thus allowing the reconstruction of spatial tissue niches.
- Kristina Handler
- , Karsten Bach
- & Andreas E. Moor
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| Open AccessRobust mapping of spatiotemporal trajectories and cell–cell interactions in healthy and diseased tissues
The integration of spatial, imaging, and sequencing information enables the mapping of cellular dynamics within a tissue. Here, authors show three algorithms in stLearn software to accurately reveal spatial trajectory, detect cell-cell interactions, and impute missing data.
- Duy Pham
- , Xiao Tan
- & Quan H. Nguyen