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| Open AccessHepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis
Activated hepatic stellate cells (aHSC) promote hepatocellular carcinoma (HCC). Here the authors show that selective ablation of stearoyl CoA desaturase-2 in aHSC suppresses leukotriene B4 receptor 2-dependent nuclear β-catenin signaling, preventing liver tumorigenesis.
- Sonal Sinha
- , Satoka Aizawa
- & Hidekazu Tsukamoto
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Article
| Open AccessType I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment
Astrocytes can influence several steps of the metastatic process in the brain. Here the authors show that type I interferon response in astrocytes facilitates brain metastasis by increasing recruitment of tumor promoting monocytic myeloid cells.
- Weili Ma
- , Maria Cecília Oliveira-Nunes
- & Qing Chen
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Article
| Open AccessMetaTiME integrates single-cell gene expression to characterize the meta-components of the tumor immune microenvironment
Integration and comparison of multiple single cell sequencing datasets can be used to compare different studies. Here the authors propose MetaTiME which compares the gene expression of single cells from the tumour microenvironment across different tumours and uses transportable labels and metacomponents to annotate cell types and states.
- Yi Zhang
- , Guanjue Xiang
- & Clifford A. Meyer
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Article
| Open AccessMethionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells
The deprivation of amino acids in the tumor microenvironment affects T cell survival and activation. Here the authors show that reduced levels of methionine are associated with PD1 upregulation in CD4+ T cells and that methionine supplementation promotes CD4+ T cell dependent anti-tumor immune responses.
- Mahesh Pandit
- , Yun-Seo Kil
- & Jae-Hoon Chang
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| Open AccessRe-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states
Glioblastoma (GBM) cells can infiltrate into the tumour microenvironment (TME) and contribute to recurrence. Here, the authors analyse primary and recurrent GBMs and their TME using single-nucleus and spatial transcriptomics, revealing tissue states defined by the combinations of neoplastic and non-neoplastic cells, which could be therapeutic targets.
- Osama Al-Dalahmah
- , Michael G. Argenziano
- & Peter Canoll
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Article
| Open AccessOvercoming adaptive resistance to anti-VEGF therapy by targeting CD5L
The efficacy of antiangiogenic therapy in the clinic is often limited by the emergence of resistance. Here, the authors show that in ovarian cancer anti-VEGF inhibitors induce the overexpression of CD5L in endothelial cells through hypoxia-driven PPARy activation and that blocking CD5L can overcome resistance.
- Christopher J. LaFargue
- , Paola Amero
- & Anil K. Sood
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Article
| Open AccessImmune cellular patterns of distribution affect outcomes of patients with non-small cell lung cancer
The spatial distribution of cellular compartments within the tumour microenvironment in non-small cell lung cancer (NSCLC) remains to be investigated. Here, the authors identify distinct cell populations of tumour cells and tumour-associated immune cell phenotypes with different spatial distributions in NSCLC.
- Edwin Roger Parra
- , Jiexin Zhang
- & Ignacio Ivan Wistuba
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Article
| Open AccessPriming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors
It has been reported that inhibition of the epigenetic regulator DNA methyltransferase 1 (DNMT1) is associated with improved response to immune checkpoint blockade (ICB). Here the authors show that conditional deletion of Dnmt1 in endothelial cells is sufficient to promote T cell infiltration, reduce tumor growth and enhance ICB response in preclinical models.
- Dae Joong Kim
- , Swetha Anandh
- & Andrew C. Dudley
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Article
| Open AccessFADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer
The role of arachidonic acid (AA) in colorectal cancer (CRC) is unclear. Here they show that FADS1-AA axis modulates the intestinal microecology by enriching gram-negative bacteria in CRC and that the altered microecology accelerates the conversion of AA to PGE2, promoting CRC tumorigenesis.
- Chunjie Xu
- , Lei Gu
- & Qing Xu
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Article
| Open AccessNasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction
Response rates to immunotherapies in patients with nasopharyngeal carcinoma (NPC) are still limited. Here the authors show that tumor-restricted CD70 correlates with regulatory T cell abundance and suppressive activity in NPC and that CD70 blockade improves response to anti-PD1 in preclinical models.
- Lanqi Gong
- , Jie Luo
- & Xin-Yuan Guan
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Article
| Open AccessMonocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma
Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.
- Zhihong Chen
- , Nishant Soni
- & Dolores Hambardzumyan
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Article
| Open AccessSmad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma
TGF-β stimulated tumor-associated neutrophils (TANs) can exert pro-tumoral functions. Here the authors show that Smad3 activation in TANs is associated with an N2-like polarization state and poor outcome in patients with non-small cell lung carcinoma and that Smad3 targeting reprograms TANs to an antitumor state suppressing tumor growth in preclinical lung cancer models.
- Jeff Yat-Fai Chung
- , Philip Chiu-Tsun Tang
- & Patrick Ming-Kuen Tang
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Article
| Open AccessSingle cell analysis in head and neck cancer reveals potential immune evasion mechanisms during early metastasis
The molecular mechanisms underlying lymph-node metastasis in head and neck squamous-cell carcinoma remain to be investigated. Here, the authors perform single-cell RNA sequencing of cancer cells and CD8 + T cells and suggest potential mechanisms of immune evasion during early metastasis.
- Hong Sheng Quah
- , Elaine Yiqun Cao
- & N. Gopalakrishna Iyer
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Article
| Open AccessContinuous Spatiotemporal Therapy of A Full-API Nanodrug via Multi-Step Tandem Endogenous Biosynthesis
Nanomedicine is important in cancer therapy, but loading, drug release, and therapeutic effectiveness issues limit the translation to the clinic. Here, authors report a full-API nanodrug with an ideal API content and pH-responsive release for continuous spatiotemporal cancer therapy based on PpIX-heme-CO/Fe2+/BV-BR metabolic pathway.
- Fang Fang
- , Sa Wang
- & Jinfeng Zhang
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Article
| Open AccessPan-cancer classification of single cells in the tumour microenvironment
The accuracy and granularity of classifying cell types in the tumour microenvironment (TME) from single-cell RNA-seq data is impacted by heterogeneity among cancer cells and similarities among functionally related immune cells. Here, the authors develop scATOMIC, a tumour and TME cell type classifier based on a hierarchical approach that can be applied to pan-cancer datasets.
- Ido Nofech-Mozes
- , David Soave
- & Sagi Abelson
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Article
| Open AccessInhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies
Hypomethylating agents, such as 5-Azacytidine (5-AZA), are standard of care for patients with myelodysplastic and myeloid malignancies, however response rates are limited and risk of relapses high. Here the authors show that inhibition of lysyl oxidases synergizes with 5-AZA to improve erythropoiesis and reduce disease burden in myelodysplastic neoplasms models.
- Qingyu Xu
- , Alexander Streuer
- & Daniel Nowak
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Article
| Open AccessIntegrated transcriptome study of the tumor microenvironment for treatment response prediction in male predominant hypopharyngeal carcinoma
Many patients with hypopharyngeal carcinoma (HPC) do not respond to first-line combination therapy. Here, the authors analyse the tumour and the tumour microenvironment of HPC patients treated with combination therapy using single-cell RNA-seq, and train a classifier to distinguish responders based on cell type composition.
- Yang Zhang
- , Gan Liu
- & Zhigang Huang
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Article
| Open AccessLYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1
The survival of chronic lymphocytic leukemia cells strongly depends on the presence of a supportive microenvironment. Here, the authors show that LYN kinase is essential for the reprogramming of stromal cells towards a leukemia-supportive phenotype that facilitates disease progression.
- Alexander F. vom Stein
- , Rocio Rebollido-Rios
- & Michael Hallek
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| Open AccessCDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy
LKB1 mutations have been associated with primary resistance to immune checkpoint inhibitors in patients with lung cancer. Here the authors show that Lkb1-deficient lung tumors are characterized by defective trafficking and adhesion of T cells and that, by upregulating ICAM1 expression, CDK4/6 inhibitors sensitize LKB1 mutant lung cancer to anti-PD1 blockade.
- Xue Bai
- , Ze-Qin Guo
- & Zhong-Yi Dong
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Article
| Open AccessA variational algorithm to detect the clonal copy number substructure of tumors from scRNA-seq data
The inference of clonal architectures in cancer using single-cell RNA-seq data remains challenging. Here, the authors develop SCEVAN, a variational algorithm for copy number-based clonal structure inference in single-cell RNA-seq data that can characterise evolution and heterogeneity in the tumour and the microenvironment.
- Antonio De Falco
- , Francesca Caruso
- & Michele Ceccarelli
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| Open AccessReconstruction of the tumor spatial microenvironment along the malignant-boundary-nonmalignant axis
Delineating the cellular composition of tumour boundaries in spatial transcriptomics (ST) data is challenging. Here, the authors develop Cottrazm to integrate ST with histological imaging and single-cell data, identify the malignant and non-malignant tissue boundaries, deconvolute cell-type composition, and reconstruct cell type-specific gene expression profiles.
- Zhenzhen Xun
- , Xinyu Ding
- & Youqiong Ye
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| Open AccessLarge-scale genomic analyses reveal alterations and mechanisms underlying clonal evolution and immune evasion in esophageal cancer
Esophageal cancers feature distinct manifestations between and within patients which complicate precision diagnosis, prognosis, and patient care. New genomic and epigenomic research uncovers novel mechanisms underlying both inter- and intra-tumoral heterogeneity in esophageal cancer, with significant biological and translational implications.
- De-Chen Lin
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Article
| Open AccessCoadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) cells can utilise the tumour microenvironment to metastasise to the liver. Here the authors show that hepatoctyes overexpress SLIT2 to enable premetastatic niche formation for ROBO1-positive PDAC cells to support the survival of these tumour cells in the liver.
- Qing Li
- , Xiao-Xin Zhang
- & Zhi-Gang Zhang
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Article
| Open AccessSingle-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis
Peritoneal metastasis is one of the most common forms of death for gastrointestinal cancers, however, its cell composition is incompletely understood. Here, the authors use single cell RNA-seq of peritoneal metastases from 35 patients and show diversity in immune cells, and plasticity in cancer cell phenotypes and autophagy related genes as biomarkers of prognosis.
- Xuan-Zhang Huang
- , Min-Jiao Pang
- & Zhen-Ning Wang
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Article
| Open AccessSingle-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
The role of therapy in shaping the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) remains to be explored. Here, the authors perform single-cell RNA sequencing in PDAC samples before and after chemotherapy and suggest that chemotherapy may promote resistance to immunotherapy.
- Gregor Werba
- , Daniel Weissinger
- & Diane M. Simeone
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Article
| Open AccessLong-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.
- Jenniffer Linares
- , Anna Sallent-Aragay
- & Alexandre Calon
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| Open AccessDissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses
The immune suppressive tumour microenvironment drives recurrence and metastatic disease in prostate cancer. Here authors provide a detailed analysis of the microenvironment via single cell RNA sequencing and high-resolution spatial transcriptomics to identify tumour-dependent changes compared to healthy tissue.
- Taghreed Hirz
- , Shenglin Mei
- & David B. Sykes
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| Open AccessEstimation of cell lineages in tumors from spatial transcriptomics data
Cell type deconvolution in tumor spatial transcriptomics (ST) data remains challenging. Here, the authors develop Spatial Cellular Estimator for Tumors (SpaCET) to infer cell types and intercellular interactions from ST data in cancer across different platforms, with improved performance over similar methods.
- Beibei Ru
- , Jinlin Huang
- & Peng Jiang
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Article
| Open AccessSingle-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer
Fibroblast heterogeneity is a prominent but poorly understood feature of solid tumours. Here three major fibroblast subpopulations in non-small cell lung cancer are identified and characterised through single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry.
- Christopher J. Hanley
- , Sara Waise
- & Gareth J. Thomas
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Article
| Open AccessIn vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma
Alveolar macrophages represent a cell type that is physiologic to the lung immune landscape, however, it is not known whether they play an active role to maintain the tumour immune microenvironment. Here authors show by single cell RNA sequencing and functional experiments, that intra-tumour alveolar macrophages are phenotypically and transcriptionally different from the healthy ones, and likely play an aetio-pathologic role in tumorigenesis.
- Seiji Taniguchi
- , Takahiro Matsui
- & Masaru Ishii
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Article
| Open AccessNiche stiffness sustains cancer stemness via TAZ and NANOG phase separation
Stromal cells in the tumour microenvironment are reported to regulate cancer stemness via biomechanical signals. Here the authors show that TAZ activated by biomechanical cues enhanced cancer stem cell properties via phase separation with Nanog.
- Xinwei Liu
- , Yingying Ye
- & Qiyi Zhao
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Article
| Open AccessOncolytic Parapoxvirus induces Gasdermin E-mediated pyroptosis and activates antitumor immunity
Oncolytic viruses are able to target tumours and thought to induce apoptosis while remodelling the tumour immune microenvironment. Here authors show in an oncolytic parapoxvirus ovis model that pyroptosis, a highly immunogenic Gasdermin-E-dependent cell death mechanism, is the dominant cell death pathway during virotherapy.
- Jing Lin
- , Shihui Sun
- & Wenqi He
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Article
| Open AccessCD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer
The origin of cancer-associated fibroblasts (CAFs) in cancer remains to be identified. Here, single-cell transcriptomics, in vivo and in vitro studies suggest that CD26+ and CD26- normal fibroblasts transform into distinct CAF subpopulations in mouse models of breast cancer.
- Julia M. Houthuijzen
- , Roebi de Bruijn
- & Jos Jonkers
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| Open AccessA comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer
T cell exhaustion in breast tumours remains to be fully characterised. Here, single cell transcriptomics and imaging mass cytometry analysis of luminal breast tumours with or without exhausted T cells suggests distinct patterns of PD-1 and CXCL13 expression in T cells, and of MHC-I, but not PD-L1, expression in tumour cells.
- Sandra Tietscher
- , Johanna Wagner
- & Bernd Bodenmiller
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| Open AccessThe splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis
Cancer-associated fibroblasts (CAFs) are the main component of the stroma in pancreatic cancer, but their tissue of origin remains to be defined. Here the authors perform lineage tracing and single cell RNA sequencing in mice and suggest the splanchnic mesenchyme as the tissue of origin for CAFs.
- Lu Han
- , Yongxia Wu
- & Gustavo Leone
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Article
| Open AccessPRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression
Tsp-1 in the tumor microenvironment is known to suppress tumor growth and progression. Here the authors show that PRSS2 represses Tsp-1 by binding to lipoprotein receptor-related protein 1 and suggest targeting PRSS2 mediated Tsp-1 repression as a potential therapeutic strategy.
- Lufei Sui
- , Suming Wang
- & Randolph S. Watnick
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Article
| Open AccessExosomal miR-1304-3p promotes breast cancer progression in African Americans by activating cancer-associated adipocytes
The molecular mechanisms explaining racial disparity in breast cancer mortality are not completely elucidated. Here, the authors show that an African-associated SNP in American breast cancer patients, leads to higher levels of microRNA miR-1304-3p which promotes cancer by increasing lipids availability.
- Dan Zhao
- , Kerui Wu
- & Kounosuke Watabe
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Article
| Open AccessBrain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer
While EGFR-targeted therapies have clinical benefit, drug-resistant brain metastases present a major obstacle. Here, the authors identify a genetic signature in brain metastatic lesions associated with osimertinib resistance and find RhoA to have an important role in the resulting phenotype.
- Sally J. Adua
- , Anna Arnal-Estapé
- & Don X. Nguyen
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Article
| Open AccessEngineered Lactococcus lactis secreting Flt3L and OX40 ligand for in situ vaccination-based cancer immunotherapy
The probiotic Lactococcus lactis has been used for the delivery of therapeutic molecules. Here the authors engineer Lactococcus lactis to express a fusion protein of Flt3L and OX40 ligand, eliciting anti-tumor immune response in preclinical cancer models.
- Junmeng Zhu
- , Yaohua Ke
- & Baorui Liu
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Article
| Open AccessSOTIP is a versatile method for microenvironment modeling with spatial omics data
Methods that analyse heterogeneity and compare tissue microenvironments using spatial omics data are challenging to develop. Here, the authors present SOTIP, a method that can perform spatial heterogeneity, spatial domain, and differential microenvironment analyses across multiple spatial omics modalities.
- Zhiyuan Yuan
- , Yisi Li
- & Michael Q. Zhang
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Article
| Open AccessARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression
The accumulation of myeloid derived suppressor cells (MDSC) has been associated with prostate cancer progression and castration resistance. Here the authors show that loss of ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, results in polymorphonuclear-MDSC infiltration and cooperates with Pten loss to accelerate prostate tumorigenesis.
- Ni Li
- , Qiuli Liu
- & Jun Qin
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Article
| Open AccesscircCsnk1g3- and circAnkib1-regulated interferon responses in sarcoma promote tumorigenesis by shaping the immune microenvironment
Circular RNAs can contribute to tumour progression. Here the authors show that two circular RNAs, circCsnk1g3 and circAnkib1 promote sarcoma growth by controlling the expression of interferon related genes and pro-inflammatory factors in sarcoma cells
- Roberta Piras
- , Emily Y. Ko
- & Jlenia Guarnerio
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Article
| Open AccessSpatially aware dimension reduction for spatial transcriptomics
Spatial transcriptomics analyses can be affected by noise and spatial correlation across tissue locations. Here, the authors develop SpatialPCA, a spatially-aware dimensionality reduction method that explicitly models spatial correlation structures, and show its application to the analysis of healthy and tumour tissues.
- Lulu Shang
- & Xiang Zhou
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Article
| Open AccessPolymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models
Nanotherapy has potential utility in cancer, particularly in targeted delivery of therapeutics. Here the authors demonstrate delivery of tranilast loaded micelles to improve the reprogramming of cancer associated fibroblasts and monitor tumour stiffness to predict responses.
- Myrofora Panagi
- , Fotios Mpekris
- & Triantafyllos Stylianopoulos
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Article
| Open AccessCancer cell survival depends on collagen uptake into tumor-associated stroma
Collagen can be a metabolic source to fuel cancer growth. Here the authors show that cell surface protein TEM8 mediates the binding and uptake of collagen in stromal cells and these cells processed the collagen to glutamine, providing an alternative energy source for tumour cells to grow.
- Kuo-Sheng Hsu
- , James M. Dunleavey
- & Brad St. Croix
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Article
| Open AccessElective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors
Neck dissection and/or elective nodal irradiation (ENI) are commonly performed in patients with head and neck squamous cell carcinoma (HNSCC) to minimize local and regional recurrence. However, here the authors show that ENI blunts the immune response to combined radiation and immunotherapy, increasing local and distant tumor growth in HNSCC preclinical models.
- Laurel B. Darragh
- , Jacob Gadwa
- & Sana D. Karam
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Article
| Open AccessStromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity
Forkhead transcription factor FoxF2 plays a crucial role in the development of organs derived from primitive gut. Here the authors show that reduction of Foxf2 expression in stromal cells is associated with high grade prostate cancer and that increasing prostatic stromal Foxf2 sensitizes prostate cancer to immune checkpoint blockade.
- Deyong Jia
- , Zhicheng Zhou
- & Li Xin
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Article
| Open AccessTumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer
Dendritic cells (DC) present tumour antigens to T cells but this process is defective in the tumour microenvironment. Here the authors find that downregulation of cholesterol 25-hydroxylase underlies defective cross presentation of tumour antigens.
- Zhen Lu
- , Jinyun Chen
- & Serge Y. Fuchs
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Article
| Open AccessPan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment
Cancer-associated fibroblasts (CAFs) are a predominant and critical component of the tumour microenvironment. Here, the authors integrate and analyse single-cell RNA-seq data of CAFs across 10 common solid cancer types, identifying their plasticity and interactions with other cell types.
- Han Luo
- , Xuyang Xia
- & Heng Xu