Featured
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| Open AccessSuppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade
Tumor associated neutrophils have been correlated with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here the authors show that the tyrosine kinase inhibitor lorlatinib modulates neutrophil development and recruitment in the tumor microenvironment, attenuating PDAC progression in preclinical mouse models.
- Sebastian R. Nielsen
- , Jan E. Strøbech
- & Janine T. Erler
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Article
| Open AccessEngineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments
The mechanics of the migration of T cells into tumours is an important aspect of tumour immunity. Here the authors engineer complex 3D environments to explore functions of microtubules and cell contractility as strategies to enhance T cell migration in tumour microenvironments.
- Erdem D. Tabdanov
- , Nelson J. Rodríguez-Merced
- & Paolo P. Provenzano
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Article
| Open AccessUltraviolet light-induced collagen degradation inhibits melanoma invasion
Ultraviolet radiation (UVR) increases melanoma incidence. Here, the authors report that UVR-damaged dermal fibroblasts upregulate MMP1 to degrade collagen which inhibits melanoma invasion and that aged primary melanomas in skin with degraded collagen have a better prognosis, while new collagen synthesis restores invasion and leads to death.
- Timothy Budden
- , Caroline Gaudy-Marqueste
- & Amaya Virós
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Article
| Open AccessDecoupling epithelial-mesenchymal transitions from stromal profiles by integrative expression analysis
Epithelial cancer cells can transition into a mesenchymal phenotype to enable invasion and metastasis. Here, the authors use previously published single-cell and bulk RNA sequencing datasets to decouple the mesenchymal expression profiles of cancer and stromal cells.
- Michael Tyler
- & Itay Tirosh
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Article
| Open AccessCo-evolution of tumor and immune cells during progression of multiple myeloma
Clonal evolution in multiple myeloma (MM) needs to be understood in both the tumor and its microenvironment. Here the authors perform single-cell multi-omics profiling of samples from MM patients at different stages, finding transitions in the immune cell composition throughout progression.
- Ruiyang Liu
- , Qingsong Gao
- & Li Ding
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Article
| Open AccessSingle-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer
Comprehensive profiles of tumour and microenvironment are critical to understand heterogeneity in non-small cell lung cancer (NSCLC). Here, the authors profile 42 late-stage NSCLC patients with single-cell RNA-seq, revealing immune landscapes that are associated with cancer subtype or heterogeneity.
- Fengying Wu
- , Jue Fan
- & Caicun Zhou
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Article
| Open AccessSuppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells
Pancreatic ductal adenocarcinoma has a collagen-rich dense extracellular matrix that promotes malignancy of cancer cells. Here, the authors show that fibrillar collagen that is cancer-cell-derived, but not stroma-derived, selectively restrains tumor growth under control of their pC-proteinase, BMP1.
- Chenxi Tian
- , Ying Huang
- & Richard O. Hynes
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Article
| Open AccessInterleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer
The stromal fibroblast population in the colon is composed of heterogeneous and distinct cell subtypes that play a crucial role in the development of colitis and colon cancer. Here the authors generate IL-11 reporter mice and characterize the origin and phenotype of inflammatory IL-11+ fibroblasts in colitis and colon cancer preclinical models.
- Takashi Nishina
- , Yutaka Deguchi
- & Hiroyasu Nakano
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Article
| Open AccessAn integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer
Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.
- Sia Viborg Lindskrog
- , Frederik Prip
- & Lars Dyrskjøt
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Article
| Open AccessThe white matter is a pro-differentiative niche for glioblastoma
Glioma stem cells (GSCs) retain the ability to partially differentiate, but it is unclear how the brain microenvironment may influence this response. Here the authors show that glioblastoma cells infiltrating into the white matter acquire pre-oligodendrocyte-like fate in a process that mimics myelin repair and results in tumour suppression
- Lucy J. Brooks
- , Melanie P. Clements
- & Simona Parrinello
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Article
| Open AccessP-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression
Glioma-associated microglia/macrophages are central drivers of brain tumor pathology. Here the authors characterize the role of the P-selectin/PSGL-1 axis in the cross-talk between glioblastoma cells and microglia/macrophages and show that the therapeutic targeting of P-selectin limits glioblastoma progression in preclinical models.
- Eilam Yeini
- , Paula Ofek
- & Ronit Satchi-Fainaro
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Article
| Open AccessComprehensive single-cell sequencing reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of nasopharyngeal carcinoma
The tumor microenvironment can influence patient survival response to therapy. Here, the authors used single-cell sequencing to investigate the microenvironment of nasopharyngeal cancer and identify tumor-specific signatures in five stromal clusters of cells that may influence patient survival.
- Lanqi Gong
- , Dora Lai-Wan Kwong
- & Xin-Yuan Guan
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Article
| Open AccessImmune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment
The use of CSF for diagnosis of metastatic brain tumors could be of clinical and patient benefit. Here the authors undertake a single-cell RNA analysis of CSF and brain to determine whether the phenotype in the CSF is reflective of the phenotype in the tumor.
- Carlota Rubio-Perez
- , Ester Planas-Rigol
- & Joan Seoane
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Article
| Open AccessTumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma
Intratumoral CD8+ T cells commonly display a dysfunctional state, however it remains unclear whether tumor cell metabolism actively promotes T-cell exhaustion. Here, the authors show that the tumor methionine recycling pathway has a central role in promoting T-cell dysfunction in hepatocellular carcinoma, contributing to tumor immune evasion.
- Man Hsin Hung
- , Joo Sang Lee
- & Xin Wei Wang
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Article
| Open AccessRNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming
N6-methyladenosine (m6A) is a reversible mRNA modification with important roles in cancer biology and immunoregulation. Here, the authors show that myeloid-specific deletion of Mettl3, the catalytic subunit of the methyltransferase complex, promotes tumor growth and metastasis in preclinical tumor models, influencing macrophage reprogramming and attenuating PD-1 blockade.
- Huilong Yin
- , Xiang Zhang
- & Rui Zhang
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Article
| Open AccessInnate immune evasion revealed in a colorectal zebrafish xenograft model
Zebrafish has emerged as an important vertebrate model to study tumor biology and immune response. Here, using a zebrafish xenograft model, the authors show that the engraftment capacity of human colorectal cancer cell lines is influenced by innate immune response and immunoediting.
- Vanda Póvoa
- , Cátia Rebelo de Almeida
- & Rita Fior
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Article
| Open AccessPlasma cells are enriched in localized prostate cancer in Black men and are associated with improved outcomes
A recent report suggested Black men with prostate cancer were more responsive to immunotherapy. Here, the authors analysed prostate cancer gene expression profiles and show tumours from Black men and men with African ancestry have an increased proportion of plasma cells compared to those of White men and this correlates with improved outcome following treatment.
- Adam B. Weiner
- , Thiago Vidotto
- & Edward M. Schaeffer
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Article
| Open AccessCAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy
Several strategies have been attempted to target immune suppressive populations in the tumor microenvironment. Here the authors show that folate receptor β-targeted CAR-T cells eliminate immunosuppressive tumor associated macrophages, promoting endogenous antitumor immune responses and adoptive T-cell therapy in pre-clinical models.
- Alba Rodriguez-Garcia
- , Rachel C. Lynn
- & Daniel J. Powell Jr.
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Article
| Open AccessBiallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma
Relapse following BCMA targeted CAR T-cell therapy is frequently observed in patients with multiple myeloma (MM). Here, by single cell transcriptome profiling on serially collected bone marrow samples, the authors report biallelic loss of BCMA as the mechanism of resistance underlying both relapse and lack of response to a second CAR T infusion in a patient with MM.
- Mehmet Kemal Samur
- , Mariateresa Fulciniti
- & Nikhil C. Munshi
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Article
| Open AccessTumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution
Nasopharyngeal carcinoma is a diverse cancer characterised by a heterogeneous microenvironment. Here, the authors use single cell sequencing to analyse the tumour microenvironment in 10 nasopharyngeal carcinoma tumours and identify different cell types including immune-suppressive T regulatory, tolerogenic dendritic, and exhausted CD8 T cells.
- Yang Liu
- , Shuai He
- & Jin-Xin Bei
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Article
| Open AccessMesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer
The effects of bone-marrow derived MSCs on prostate cancer cells remain unknown. Here the authors show that MSC-derived IL-28 induces prostate cancer cell apoptosis via IL-28Rα-STAT1 signalling, while acquired resistance to apoptosis is associated with a shift in IL-28Rα signalling via STAT1 to STAT3.
- Jeremy J. McGuire
- , Jeremy S. Frieling
- & Conor C. Lynch
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Article
| Open AccessStromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth
The tumor microenvironment is composed of many cell types that crosstalk to modulate local immunity. Here the authors show that Amyloid β proteins from cancer-associated fibroblasts (CAF) induce neutrophil extracellular trap (NET) production by neutrophils, while NET feeds back to activate CAF, thereby implicating Amyloid β as a potential therapy target.
- Hafsa Munir
- , James O. Jones
- & Jacqueline D. Shields
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Article
| Open AccessBoosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles
Durable response rate to anti-PD-1/PD-L1 therapy remains relatively low in patients with cancer. Here the authors show that metformin-loaded mannose-modified macrophage-derived microparticles reprogram the tumor immune microenvironment and improve responses to anti-PD-1 therapy.
- Zhaohan Wei
- , Xiaoqiong Zhang
- & Xiangliang Yang
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Article
| Open AccessIntratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma
Intratumoural heterogeneity is a feature of liver cancer. Here, the authors demonstrate that heterogeneity exists at the immune cell level in liver cancer and show that tumours with high intratumoural immune heterogeneity demonstrated an immune suppressive microenvironment, which was associated with tumour evolution and a poor prognosis.
- Phuong H. D. Nguyen
- , Siming Ma
- & Valerie Chew
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Article
| Open AccessPredicting postoperative peritoneal metastasis in gastric cancer with serosal invasion using a collagen nomogram
Gastric cancer can metastasise to the peritoneal cavity; predicting in which patients this will occur is important for clinical management of the disease. Here, the authors use multi-photon imaging to derive a collagen signature of the primary cancer that allows the prediction of metastasis.
- Dexin Chen
- , Zhangyuanzhu Liu
- & Jun Yan
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Article
| Open AccessIdentification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease characterized by an immunosuppressive microenvironment. Here the authors show that a subset of P2RX1-negative neutrophils with immunosuppressive properties accumulate in PDAC metastatic liver tissues and promote tumor growth.
- Xu Wang
- , Li-Peng Hu
- & Zhi-Gang Zhang
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Article
| Open AccessFerroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway
Ferroptosis is an iron-dependent mechanism of cell death. In this mouse study, the authors show that diets high in iron or depletion of the antioxidant Gpx4 potentiates pancreatic damage and tumour formation by activating the DNA damage pathway and recruiting macrophages to the pancreas.
- Enyong Dai
- , Leng Han
- & Daolin Tang
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Article
| Open AccessSingle-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma
Osteosarcomas are difficult to treat and have a limited response to immunotherapy. Here, the authors analyse osteosarcomas at the single-cell level, and identify both the transdifferentiation of malignant cells and an array of immune cells that could have implications for metastasis and immunotherapy.
- Yan Zhou
- , Dong Yang
- & Haiyan Hu
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Article
| Open AccessHIF1A signaling selectively supports proliferation of breast cancer in the brain
The mechanisms underlying the growth of breast cancer metastasis in the brain are unclear. Here, the authors use an intracranial injection mouse model and single-cell analysis of patient circulating tumour cells to demonstrate that increased hypoxic and HIF1A signalling promotes tumour growth in the brain.
- Richard Y. Ebright
- , Marcus A. Zachariah
- & Shyamala Maheswaran
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Article
| Open AccessImmune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment
Understanding the tumour microenvironment is essential for the efficacy of immunotherapies. Here the authors describe the immune landscape in esophageal squamous cell carcinoma and suggest several immunosuppressive mechanisms, which upon targeting may restore anti-tumour immune response.
- Yingxia Zheng
- , Zheyi Chen
- & Lisong Shen
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Article
| Open AccessHeat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer
Expression and activation of Heat shock factor 1 (HSF1) in cancer associated fibroblasts have been associated with protumorigenic functions. Here the authors show that, in a model of colitis-induced colorectal cancer, HSF1 is activated in stromal fibroblasts in the early stages of inflammation, leading to extracellular matrix remodelling that sustains tumor initiation and progression.
- Oshrat Levi-Galibov
- , Hagar Lavon
- & Ruth Scherz-Shouval
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Article
| Open AccessTumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma
The tumour microenvironment (TME) has a major role in chemoresistance in multiple myeloma. The authors show that a nanoparticle targeted to TME and loaded with bortezomib (BTZ) and Y27632 is more effective than free drugs, non-targeted and single-agent controls and reduces BTZ-related side effects.
- Cinzia Federico
- , Kinan Alhallak
- & Abdel Kareem Azab
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Article
| Open AccessCellular and gene signatures of tumor-infiltrating dendritic cells and natural-killer cells predict prognosis of neuroblastoma
Tumour-infiltrating lymphocytes play a crucial role in neuroblastoma, but their relationship to other immune cells is poorly understood. Here the authors identify the cellular and gene signatures of intratumoural dendritic cells and natural killer cells that predict the clinical outcome of neuroblastoma.
- Ombretta Melaiu
- , Marco Chierici
- & Doriana Fruci
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Article
| Open AccessNeutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression
Tumour necrosis is associated with tumour aggressiveness and poor outcomes in patients with glioblastomas, but the underlying mechanisms remain poorly understood. Here, the authors show that in a xenograft mouse model of glioblastoma, tumour-infiltrating neutrophils amplify necrosis by promoting myeloperoxidase-induced tumour cell ferroptosis.
- Patricia P. Yee
- , Yiju Wei
- & Wei Li
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Article
| Open AccessOvercoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s
Strategies to increase T cell infiltration within the tumor microenvironment could improve response to immune checkpoint blockade. Here the authors show that a combinatorial regimen based on Flt3L, radiotherapy, and TLR3/CD40 stimulation promotes intratumoral conventional type-1 dendritic cell (cDC1) activation and T cell infiltration, overcoming resistance to PD-L1 blockade.
- Takaaki Oba
- , Mark D. Long
- & Fumito Ito
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Article
| Open AccessNOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin
The presence of genomic alterations in cancer associated fibroblasts (CAFs) is largely unexplored. The authors show that frequent NOTCH1 gene amplification and overexpression render CAFs resistant to the UVA-induced DNA damage response (DDR) and promote cancer/stromal cells expansion, which can be reversed by NOTCH inhibition.
- Atul Katarkar
- , Giulia Bottoni
- & G. Paolo Dotto
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Review Article
| Open AccessConcepts of extracellular matrix remodelling in tumour progression and metastasis
Tumors are more than cancer cells — the extracellular matrix is a protein structure that organizes all tissues and is altered in cancer. Here, the authors review recent progress in understanding how the cancer cells and tumor-associated stroma cells remodel the extracellular matrix to drive tumor growth and metastasis.
- Juliane Winkler
- , Abisola Abisoye-Ogunniyan
- & Zena Werb
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Article
| Open AccessSingle-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma
Bladder urothelial carcinoma is one of the most prevalent urogenital cancer types with limited therapeutic options. Here, the authors characterize the tumor immune microenvironment of bladder cancer using single cell RNA sequencing and suggest a role for inflammatory cancer-associated fibroblasts in tumor progression.
- Zhaohui Chen
- , Lijie Zhou
- & Ke Chen
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Article
| Open AccessGlioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression
Elevated levels of interleukin-33 have been associated with poor prognosis in patients with glioma. Here the authors show that glioma-derived IL-33 modulates a pro-tumorigenic immune microenvironment by activating resident and recruiting peripheral innate immune cells.
- Astrid De Boeck
- , Bo Young Ahn
- & Donna L. Senger
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Article
| Open AccessPINCH-1 regulates mitochondrial dynamics to promote proline synthesis and tumor growth
Proline metabolism is crucial to tumor proliferation. Here, the authors show PINCH-1 deficiency inhibited proline synthesis by promoting mitochondrial fragmentation via DRP1, downregulating PYCR1 expression and reducing cell proliferation in vitro and in vivo.
- Ling Guo
- , Chunhong Cui
- & Chuanyue Wu
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Article
| Open AccessPD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade
The role of PD-L1 expression on tumor-infiltrating immune cells in promoting tumor immune escape is not fully understood. Here, the authors show that PD-L1 expression by dendritic cells plays a crucial role in hindering anti-tumor T cell responses and is essential for the therapeutic efficacy of PD-L1 blockade.
- Qi Peng
- , Xiangyan Qiu
- & Haidong Tang
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Article
| Open AccessCollagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion
Tumor extracellular matrix has been associated with cancer progression, therapy resistance and immune suppression. Here, the authors show that collagen generates resistance to PD-1/PD-L1 immunotherapy by upregulating LAIR1 expression and downstream signaling, leading to increased CD8+ T cell exhaustion.
- David H. Peng
- , Bertha Leticia Rodriguez
- & Don L. Gibbons
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Article
| Open AccessAndrogen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion
Anti-androgen therapy inhibits prostate cancer (PC) progression, and is thought to act directly on cancer cells. Here the authors show that androgen receptor is expressed on normal and PC-associated macrophages, and its stimulation alters macrophage secretome to promote migration of cultured PC cell lines.
- Bianca Cioni
- , Anniek Zaalberg
- & Andries M. Bergman
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Article
| Open AccessDual roles of neutrophils in metastatic colonization are governed by the host NK cell status
The role of neutrophils in the regulation of tumour growth and metastasis remains controversial. Here, the authors demonstrate that neutrophils, by exerting inhibitory effects on cytotoxic NK cells, show a net pro-metastatic effect in immune-competent mice, while they are tumoricidal and anti-metastatic in NK cell-deficient hosts.
- Peishan Li
- , Ming Lu
- & Guangwen Ren
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Article
| Open AccessFGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy
Macrophages contribute to tumour progression and response to therapy. Here, the authors show that absence of FGF2 in the tumour microenvironment reduces tumour growth and enhances the anti-tumour immune response by altering macrophage polarization. As a result, disruption of this macrophage programming by anti-FGF2 blocking antibodies enhances the outcome from radiotherapy.
- Jae Hong Im
- , Jon N. Buzzelli
- & Ruth J. Muschel
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Article
| Open AccessBlockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine
The tryptophan metabolite kynurenine is an endogenous ligand of the aryl hydrocarbon receptor (AHR). Here, the authors show that AHR targeting in IDO/TDO-expressing tumours counteracts a regulatory T cell/macrophage suppressive axis and synergizes with immune checkpoint blockade to hinder tumour growth.
- Luis Felipe Campesato
- , Sadna Budhu
- & Jedd D. Wolchok
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Article
| Open AccessMutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome
p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions. In this study, the authors demonstrate a novel mutant-p53/HIF1α/miR-30d axis that impacts Golgi structure, trafficking, and secretion of proteins essential for tumor growth and metastasis.
- Valeria Capaci
- , Lorenzo Bascetta
- & Giannino Del Sal
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Article
| Open AccessSingle-cell transcriptomic analysis in a mouse model deciphers cell transition states in the multistep development of esophageal cancer
The multistep processes involved in the evolution of inflammation to invasive esophageal squamous cell carcinoma (ESCC) is unclear. Here, the authors report a mouse model of ESCC and the role of interplay between carcinogen-transformed epithelial cells and their microenvironment in ESCC development.
- Jiacheng Yao
- , Qionghua Cui
- & Jianbin Wang
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Comment
| Open AccessTargeting adhesion to the vascular niche to improve therapy for acute myeloid leukemia
Niche hijack by malignant cells is considered to be a prominent cause of disease relapse. Barbier and colleagues uncover (E)-selectin as a novel mediator of malignant cell survival and regeneration which, upon blockade, has the potential to significantly improve therapeutic outcomes.
- Myriam L. R. Haltalli
- & Cristina Lo Celso