Featured
-
-
Article
| Open AccessMYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling
Tripe-negative breast cancers poorly respond to immune checkpoint inhibition therapy, due to their immune-hostile tumour microenvironment. Authors here show that the oncogene MYC plays a pivotal role in suppressing anti-tumour immunity via directly regulating the transcription of interferon signalling genes.
- Dario Zimmerli
- , Chiara S. Brambillasca
- & Jos Jonkers
-
Article
| Open AccessBRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling
Cancer-associated fibroblasts are transcriptionally rewired by signals from the cancer cells, resulting in heterogeneous populations. Here the authors show that loss of BRCA function in pancreatic cancer cells leads to HSF1–dependent accumulation of immune-regulatory clusterin-positive cancer associated fibroblasts.
- Lee Shaashua
- , Aviad Ben-Shmuel
- & Ruth Scherz-Shouval
-
Article
| Open AccessPD-L1-directed PlGF/VEGF blockade synergizes with chemotherapy by targeting CD141+ cancer-associated fibroblasts in pancreatic cancer
A desmoplastic stroma, enriched in cancer-associated fibroblasts (CAF), has been associated with resistance to therapy in patients with pancreatic ductal adenocarcinoma (PDAC). Here, after showing that chemotherapy promotes tumor fibrosis by increasing CAF frequency and activity, the authors develop a multi-paratopic VEGF decoy receptor for PD-L1 directed PlGF/VEGF blockade, promoting anti-fibrotic and anti-tumor effects in PDAC models.
- Duk Ki Kim
- , Juhee Jeong
- & Keehoon Jung
-
Article
| Open AccessSingle-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma
Many aspects of the tumourigenesis of endometrioid endometrial cancers (EEC) are still poorly understood. Here, the authors use single-cell transcriptomics to characterise EEC tumours and their microenvironment across different stages, and reveal potential cells of origin for EEC.
- Xiaojun Ren
- , Jianqing Liang
- & Xiaojun Chen
-
Article
| Open AccessBlood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma
Tumor-associated macrophages are believed to promote tumour progression and to hamper immune therapy in gliomas. Here authors identify a distinct population of macrophages within the glioblastoma immune microenvironment with antitumour properties and clearly distinguishable phenotypes and gene expression patterns from tumour promoting macrophages.
- Hyun-Jin Kim
- , Jang Hyun Park
- & Heung Kyu Lee
-
Article
| Open AccessTumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression
Methylmalonic acid (MMA) is increased in aging as well as produced by advanced tumors, and can drive pro-aggressive changes in these tumor cells. Here, the authors show that MMA can also act on fibroblasts in the tumor microenvironment, recruiting and activating them to further support tumor progression.
- Zhongchi Li
- , Vivien Low
- & John Blenis
-
Article
| Open AccessReprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma
Myeloid cells contribute to the tumor microenvironment of thyroid cancers, but their functional relevance is lesser known. Here authors show that myeloid cells infiltrating non-medullary thyroid carcinomas upregulate their antigen presentation-related genes, release less cytokines and over-produce reactive oxygen species, with transcriptional changes already present in extra-tumoral myeloid cells.
- Katrin Rabold
- , Martijn Zoodsma
- & Romana T. Netea-Maier
-
Article
| Open AccessFibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system
Fibrocytes are monocyte-derived cells implicated in wound healing. Here, the authors utilise single cell RNA-seq, genetic ablation and multiplexed imaging to identify a fibrocyte population in lung cancer models, and use human lung cancer coculture systems to highlight their potential to modulate microenvironmental niche and sensitivity to endothelin blockade.
- Andreas Weigert
- , Xiang Zheng
- & Rajkumar Savai
-
Article
| Open AccessTGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine
TGF-β has been shown to regulate stem-like CD8 + T cell differentiation into tissue resident memory T cells in chronic infection. Here authors show that in tumour-bearing mice, a similar TGF-βdependent CD8 + T cell differentiation program is carried out in the draining lymph nodes, which impedes generation of anti-tumor migratory effector T cells upon future vaccination.
- Guo Li
- , Saranya Srinivasan
- & Nu Zhang
-
Article
| Open AccessSingle cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease
The molecular and cellular underpinnings of cribriform prostate cancer aggressiveness remain to be explored. Here, the authors perform single-cell RNA-sequencing, TCR sequencing and histology and reveal cancer cell intrinsic pathways and an immunosuppressive tumour microenvironment.
- Hong Yuen Wong
- , Quanhu Sheng
- & Paula J. Hurley
-
Article
| Open AccessMolecular characterization of renal cell carcinoma tumors from a phase III anti-angiogenic adjuvant therapy trial
Based on the S-TRAC results, sunitinib is approved as adjuvant treatment for adult patients at high risk of recurrent RCC following nephrectomy. Here, the authors report the results of an integrated multi-omics tumor analysis of 171 patients from the trial and identify specific molecular subtypes as well as potential new targets.
- Robert J. Motzer
- , Jean-François Martini
- & Alain Ravaud
-
Article
| Open AccessThe spatial transcriptomic landscape of non-small cell lung cancer brain metastasis
Brain metastases (BrMs) in non-small cell lung cancer (NSCLC) are associated with dismal outcomes, and are possibly sustained by the brain microenvironment. Here, the authors analyse NSCLC BrMs using Digital Spatial Profiling and reveal fibrosis, immune suppression, and cell reprogramming in the BrM microenvironment.
- Qi Zhang
- , Rober Abdo
- & Shawn Shun-Cheng Li
-
Article
| Open AccessZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer
Cancer-associated fibroblasts (CAFs) have been implicated in lung cancer chemo-resistance. Here the authors show that a zinc-transporter positive CAF subset is enriched in lung cancer models after chemotherapy and actively transfers zinc to cancer cells, promoting ABCB1-mediated chemo-resistance.
- Chen Ni
- , Xiaohan Lou
- & Zhihai Qin
-
Article
| Open AccessMultiscale profiling of protease activity in cancer
The activity of multiple enzymes is dysregulated in cancer, but this cannot always be measured through enzyme expression. Here, the authors develop methods to measure protease activity across the organism, tissue, and single cell scales, and identify protease dysregulation in lung cancer and its response to targeted therapy.
- Ava P. Amini
- , Jesse D. Kirkpatrick
- & Sangeeta N. Bhatia
-
Article
| Open AccessChemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer
Accumulating evidence suggest that chemotherapy could paradoxically promote cancer metastasis. Here the authors report that, in preclinical breast cancer models, adjuvant treatment with doxorubicin induces the formation of an immunosuppressive metastatic niche that promotes relapse but that can be reverted with pharmacological blockade of complement signaling.
- Lea Monteran
- , Nour Ershaid
- & Neta Erez
-
Article
| Open AccessCD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis
Macrophage-mediated immune suppression contributes to poor outcome in liver metastasis. Here the authors show that CD36-expressing metastasis associated macrophages engulf tumor cell-derived extracellular vesicles enriched in long-chain fatty acids, acquiring a pro-tumorigenic phenotype in a preclinical liver metastasis model.
- Ping Yang
- , Hong Qin
- & Xiong Z. Ruan
-
Article
| Open AccessA transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma
Metastatic clear cell renal cell carcinoma has a poor prognosis. Here, the authors use single cell RNA-seq to show a distinct gene expression signature in the primary tumour of metastatic patients, and highlights immune cell receptor interactions as potential therapeutic targets.
- Adele M. Alchahin
- , Shenglin Mei
- & Ninib Baryawno
-
Article
| Open AccessA protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses
Manganese has a crucial role in cGAS-STING-mediated DNA sensing and has emerged as a STING agonist. Here the authors report the design and characterization of a nanosystem incorporating manganese ions and the chemotherapeutic drug β-lapachone, inducing T-cell mediated anti-tumor immune responses in preclinical cancer models.
- Xuan Wang
- , Yingqi Liu
- & Zhong Luo
-
Article
| Open AccessUSP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer
IDO1-mediated tryptophan metabolism plays an important role in creating an immunosuppressive tumour microenvironment. Here, the authors show that deubiquitinase USP14 regulates immune suppression by inducing IDO1 stabilization and suggest USP14 as a potential therapeutic target to improve immunotherapy in colorectal cancer.
- Dongni Shi
- , Xianqiu Wu
- & Wenting Liao
-
Article
| Open AccessThe immune landscape of human thymic epithelial tumors
Thymic epithelial tumours represent a heterogenous group of malignancies with varied immune cell infiltration and prognosis. Here authors systematically analyze the phenotypes of both epithelial and immune cells that form these tumours, and identify three major subtypes with different T cell involvement that might affect prognosis.
- Zhongwei Xin
- , Mingjie Lin
- & Pin Wu
-
Article
| Open AccessMild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells
Obesity and inflammation have been associated to cancer progression. Here, the authors show that high fat and cholesterol diet, in a non-obese context, promotes tumourigenesis through increasing inflammatory monocytes and myeloid-derived pro-angiogenic factors.
- Thi Tran
- , Jean-Remi Lavillegrand
- & Stephane Potteaux
-
Article
| Open AccessTargeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors
A substantial proportion of HER2+ breast cancer patients do not benefit from HER2-targeted therapy. Here, the authors identify a population of cancer-associated fibroblasts involved in the suppression of trastuzumab-induced ADCC that can be pharmacologically targeted to raise treatment effectiveness in unresponsive tumors.
- Elisa I. Rivas
- , Jenniffer Linares
- & Alexandre Calon
-
Article
| Open AccessIn vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response
Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
- Aditi Sahu
- , Kivanc Kose
- & Milind Rajadhyaksha
-
Article
| Open AccessOXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling
Worst pattern of invasion (WPOI) is a parameter used to quantify tumor invasiveness of oral squamous cell carcinoma (OSCC). Here the authors show that a fibroblast subset characterized by the expression of the oxytocin receptor is enriched in highly invasive WPOI 4-5 OSCC tumors and can be targeted to reduce the desmoplastic stroma and tumor metastasis.
- Liang Ding
- , Yong Fu
- & Yanhong Ni
-
Article
| Open AccessNoninvasive imaging of the tumor immune microenvironment correlates with response to immunotherapy in gastric cancer
Tumour microenvironment has been linked with immunotherapy response in gastric cancer. Here, the authors use CT-based radiomics to predict neutrophils-to-lymphocyte ratio and response to immunotherapy.
- Weicai Huang
- , Yuming Jiang
- & Guoxin Li
-
Article
| Open AccessMidkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment
The tumour microenvironment in mTORC1 hyperactive cancers remains poorly characterised. Here, integrative analysis in tuberous sclerosis complex tumours with mTORC1 hyperactivity suggests distinct cell states associated with rapamycin resistance and immune modulation.
- Yan Tang
- , David J. Kwiatkowski
- & Elizabeth P. Henske
-
Article
| Open AccessSelective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling
Tumor loss of IFN-γ signalling is a major mechanism of resistance to immune checkpoint blockers. Here the authors report that melanoma cells with knockout of IFNγR1 show constitutive JAK1/2 activation and that the JAK1/2 inhibitor ruxolitinib can overcome resistance to anti-CTLA-4 therapy.
- Hongxing Shen
- , Fengyuan Huang
- & Lewis Zhichang Shi
-
Article
| Open AccessIntegrated multi-omics reveals cellular and molecular interactions governing the invasive niche of basal cell carcinoma
The role of reciprocal tumour-stroma interactions in tumour invasion remains poorly characterised. Here, single-cell and spatial transcriptomics identifies the cell populations and their transcriptional reprogramming contributing to the spatial organization of the basal cell carcinoma invasive niche.
- Laura Yerly
- , Christine Pich-Bavastro
- & François Kuonen
-
Article
| Open AccessSingle cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma
The components of the glioma immune microenvironment and their roles in promoting tumourigenesis remain poorly understood. Here, the use of single-cell RNA sequencing and multiplexed tissue-imaging in adult and pediatric high-grade gliomas reveals the activity and spatial organization of the immunomodulatory purinergic signaling pathway.
- Shannon Coy
- , Shu Wang
- & Sandro Santagata
-
Article
| Open AccessA single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma
The immune cell constituents and localisation within human hepatocellular carcinoma is not fully understood. Here the authors use single cell RNA sequencing of HCC from four different tissue sites and show differences between primary and metastatic tumours, tumour associated macrophages and immune cell populations.
- Yiming Lu
- , Aiqing Yang
- & Gangqiao Zhou
-
Article
| Open AccessTemporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis
The distribution and organisation of matrix molecules in the tumour stroma help shape solid tumour progression. Here they perform temporal proteomic profiling of the matrisome during breast cancer progression and show that collagen XII secreted from CAFs provides a pro-invasive microenvironment.
- Michael Papanicolaou
- , Amelia L. Parker
- & Thomas R. Cox
-
Article
| Open AccessCancer immune therapy using engineered ‛tail-flipping’ nanoliposomes targeting alternatively activated macrophages
Tumor-associated macrophages are mostly pro-tumorigenic, due to their re-programming by the tumor microenvironment. Here authors show that nanoliposomes, incorporating phospholipids with a flipping-tail chain, are engulfed specifically by intratumoral, alternatively activated macrophages, while delivering a cargo that converts these cells into anti-tumor macrophages.
- Praneeth R. Kuninty
- , Karin Binnemars-Postma
- & Jai Prakash
-
Article
| Open AccessProteomic analysis reveals key differences between squamous cell carcinomas and adenocarcinomas across multiple tissues
Squamous cell carcinomas are an aggressive cancer type which can occur in multiple organ systems. Here, the authors analyse the proteome of SCC cancers from 17 organs and show commonly dysregulated proteins independent of location.
- Qi Song
- , Ye Yang
- & Yingyong Hou
-
Article
| Open AccessHepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells
Ras mutations induce cell competition and cellular senescence to inhibit the proliferation of oncogenic mutated cells. Here the authors demonstrate that cellular senescence inhibits cell competition-induced elimination of oncogenic cells through HGF signalling.
- Nanase Igarashi
- , Kenichi Miyata
- & Akiko Takahashi
-
Article
| Open AccessHRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors
Lack of CD8+ T-cell infiltration into solid tumors is associated with poor responsiveness to immune checkpoint therapy (ICT). Here, the authors show that blocking the phosphorylation of HRS to reduce the induction of immunosuppressive exosomes promotes CD8+ T-cell infiltration into tumors and enhances the efficacy of ICT in mouse melanoma models.
- Lei Guan
- , Bin Wu
- & Wei Guo
-
Article
| Open AccessPro-inflammatory cytokines mediate the epithelial-to-mesenchymal-like transition of pediatric posterior fossa ependymoma
The molecular mechanisms underlying ependymoma tumorigenesis remain poorly understood. Here, single cell analysis of posterior fossa primary tumours and distal metastases highlights the role of pro-inflammatory cytokines in promoting epithelial-to-mesenchymal-transition.
- Rachael G. Aubin
- , Emma C. Troisi
- & Pablo G. Camara
-
Article
| Open AccessGlutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors
Small molecules that target RNA Polymerase I inhibit ribosome biogenesis to activate p53 through the nucleolar surveillance response pathway. Here, the authors show that p53 induction by ribosome stress is dependent on extracellular glutamine availability.
- Melvin Pan
- , Christiane Zorbas
- & Tsuyoshi Osawa
-
Article
| Open AccessOsteocyte CIITA aggravates osteolytic bone lesions in myeloma
Osteocytes play an important role in the development and progression of tumour-associated bone disease. Here the authors report an interaction between malignant plasma cells and osteocytes in multiple myeloma and show that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions.
- Huan Liu
- , Jin He
- & Jing Yang
-
Article
| Open AccessSpatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression
It is essential to improve our understanding of the features that influence aggressiveness and invasion in high grade gliomas (HGG). Here, the authors characterize dynamic anatomical structures in HGG called oncostreams, which are associated with tumor growth and are regulated by COL1A1.
- Andrea Comba
- , Syed M. Faisal
- & Pedro R. Lowenstein
-
Article
| Open AccessHomophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation
Direct contact between tumour cells and fibroblasts influences tumour cell behaviour. Here the authors show that pancreatic cancer cells and fibroblasts directly interact via homophilic ATP1A1 binding, which induces fibroblasts to secrete activin A to promote epithelial-mesenchymal transition of tumour cells and myofibroblast activation.
- Yi-Ing Chen
- , Chin-Chun Chang
- & Wen-Hwa Lee
-
Article
| Open AccessPredicting cancer prognosis and drug response from the tumor microbiome
Computational approaches have been developed to estimate tumor microbial abundances from whole genomic and RNA-sequencing datasets. Here the authors report the predictive value of tumor microbial abundance, alone or in combination with gene expression data, for cancer prognosis and drug response.
- Leandro C. Hermida
- , E. Michael Gertz
- & Eytan Ruppin
-
Article
| Open AccessPRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression
Cancer associated fibroblasts are an important and highly heterogeneous component of the tumor microenvironment. Here the authors identify PRRX1 as a master transcription factor determining a fibroblast lineage with myofibroblastic phenotype, associated with unfavourable prognosis in several cancer types.
- Keun-Woo Lee
- , So-Young Yeo
- & Seok-Hyung Kim
-
Article
| Open AccessRapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ
Pancreatic intraepithelial neoplasia (PanIN) can develop into pancreatic ductal adenocarcinoma (PDAC), however, the factors which determine how this occurs are unknown. Here, the authors illustrate the role of PPARδ in the upregulation of CCL2, resulting in an immunosuppressive microenvironment, and driving the progression of PanIN to PDAC.
- Yi Liu
- , Yasunori Deguchi
- & Imad Shureiqi
-
Article
| Open AccessEnvironmental cues from neural crest derivatives act as metastatic triggers in an embryonic neuroblastoma model
Neuroblastoma is characterised by cell types that feature mesenchymal like or sympathetic noradrenergic transcriptional profiles. Here, the authors show that exogenous factors secreted by sympathetic ganglion cells modulate these profiles, activating gene programs promoting the metastatic process.
- Dounia Ben Amar
- , Karine Thoinet
- & Valérie Castellani
-
Article
| Open AccessHypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma
Ewing sarcoma tumour cells frequently metastasize to the bone but the molecular mechanisms governing this process are not well understood. Here, the authors show that neuropeptide Y/Y5 receptor pathway is activated in the hypoxic tumour microenvironment, which results in cytokinesis defects and chromosomal instability, leading to bone invasion.
- Congyi Lu
- , Akanksha Mahajan
- & Joanna Kitlinska
-
Article
| Open AccessPD-L1 signaling selectively regulates T cell lymphatic transendothelial migration
The Programmed death-1 (PD-1) and its ligand PD-L1 are critical checkpoints in the regulation of immune responses. Here the authors implicate PD-L1 signalling at lymphatic endothelium in the regulation of transendothelial migration of T cells.
- Wenji Piao
- , Lushen Li
- & Jonathan S. Bromberg
-
Article
| Open AccessSympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer
The autonomic nervous systems densely innervate the pancreas, but its contribution to pancreatic ductal adenocarcinoma (PDAC) progression is not fully understood. Here, the authors characterize the pattern of sympathetic innervation by 3D imaging in a murine model of PDAC and show that sympathectomy aggravates cancer progression.
- Jérémy Guillot
- , Chloé Dominici
- & Fanny Mann
-
Article
| Open AccessPD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity
Phenotypic and functional states of dendritic cells critically influence the outcome of cancer and inflammation. Authors here show by single cell transcriptomics and in vitro validation assays that dichotomous PD-L1 and ICOSL expression assign dendritic cells to secretory and helper functions, with respective predominance of inflammatory cytokine expression or T helper cytokine induction.
- Caroline Hoffmann
- , Floriane Noel
- & Vassili Soumelis
-
Article
| Open AccessSingle-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer
Tumour microenvironment profiling during colorectal cancer progression may enable the discovery of therapeutic targets. Here, single cell and spatial RNA sequencing of tumour and adjacent normal tissues reveals an interaction between FAP+ fibroblasts and SPP1+ macrophages that could be disrupted as an immunotherapy strategy.
- Jingjing Qi
- , Hongxiang Sun
- & Bing Su