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| Open AccessNMR and MS reveal characteristic metabolome atlas and optimize esophageal squamous cell carcinoma early detection
Metabolic changes often occur during the early stages of cancer development. Here, the authors develop metabolomics signatures from tissues, pre- and post-operative sera and urines in esophageal squamous cell carcinoma, which may aid in early diagnosis.
- Yan Zhao
- , Changchun Ma
- & Yan Lin
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Article
| Open AccessEnabling large-scale screening of Barrett’s esophagus using weakly supervised deep learning in histopathology
Diagnosis of Barrett’s esophagus depends on pathologist assessment of stained slides. Here, the authors utilise a deep learning approach to prioritize potential cases using diagnostic labels in two datasets, with the aim to improve Barrett’s screening capacity.
- Kenza Bouzid
- , Harshita Sharma
- & Javier Alvarez-Valle
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Article
| Open AccessGenomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma
Genome complexity is a distinguishing feature of advanced cancers in contrast to precancerous conditions. Here, by analysing chromosomal copy-number evolution in early cancers and precancerous lesions of the oesophagus, the authors reveal signatures of ongoing chromosomal instability and its role in promoting tumour progression.
- Chunyang Bao
- , Richard W. Tourdot
- & Cheng-Zhong Zhang
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| Open AccessSpatial transcriptomics analysis of esophageal squamous precancerous lesions and their progression to esophageal cancer
Understanding the molecular changes in the transition from esophageal squamous precancerous lesions (ESPL) to esophageal squamous cell carcinoma (ESCC) remains essential. Here, the authors analyze ESPL samples using spatial transcriptomics and reveal expression changes in TAGLN2 and CRNN during progression to ESCC.
- Xuejiao Liu
- , Simin Zhao
- & Zigang Dong
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Article
| Open AccessMutational signature dynamics shaping the evolution of oesophageal adenocarcinoma
It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.
- Sujath Abbas
- , Oriol Pich
- & Maria Secrier
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Article
| Open AccessThe transcriptional landscape and diagnostic potential of long non-coding RNAs in esophageal squamous cell carcinoma
Esophageal squamous cell carcinoma is difficult to detect at early stages, and late detection is often linked to poor prognosis. Here, the authors develop a lncRNA signature predictive of ESCC and validate across multiple external cohorts.
- Meng Zhou
- , Siqi Bao
- & Zhihua Liu
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Article
| Open AccessMulti-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy
It remains critical to understand the genomic events in response to treatment of oesophageal adenocarcinoma (OAC). Here, the authors perform a multi-omics analysis of OAC patients from the DOCTOR phase II clinical trial, finding genomic features and immune clusters associated with survival.
- Marjan M. Naeini
- , Felicity Newell
- & Nicola Waddell
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Article
| Open AccessIntegrative proteogenomic characterization of early esophageal cancer
The progression of oesophageal squamous cell carcinoma (ESCC) from early to advanced stages requires comprehensive molecular characterisation. Here, the authors perform a proteogenomics analysis of ESCC patient samples across nine histopathological stages and three phases, identifying key alterations and paths for progression.
- Lingling Li
- , Dongxian Jiang
- & Chen Ding
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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 AccessTracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing
It is essential to understand heterogeneity and evolution at different omics levels in oesophageal squamous cell carcinoma (ESCC). Here, the authors use multi-omics to analyse heterogeneity and evolution in ESCC patient samples, and characterise the levels of immune infiltration as well as selective pressure from the tumour microenvironment.
- Sijia Cui
- , Nicholas McGranahan
- & Shixiu Wu
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Article
| Open AccessIntegrative proteomic characterization of adenocarcinoma of esophagogastric junction
The molecular subtypes of adenocarcinoma of the esophagogastric junction (AEG) remain to be identified. Here, the authors perform proteogenomic characterisation of AEG tumours with paired normal adjacent tissues and suggest three proteomic subtypes and potential druggable targets.
- Shengli Li
- , Li Yuan
- & Xiang-Dong Cheng
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Article
| Open AccessCharacterization of somatic structural variations in 528 Chinese individuals with Esophageal squamous cell carcinoma
The biological and clinical implications of high genome instability in esophageal squamous cell carcinoma (ESCC) remain to be explored. Here, the authors analyse 528 whole genomes and investigate the landscape and molecular mechanisms underlying structural variations in ESCC patients.
- Heyang Cui
- , Yong Zhou
- & Qimin Zhan
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Article
| Open Accessp53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition
Ageing normal oesophagus epithelium contains p53 mutant clones. Here the authors use transgenic mice to show how these clones form and contribute to cancer development.
- Kasumi Murai
- , Stefan Dentro
- & Philip H. Jones
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Article
| Open AccessIntegrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics
The mutational landscape of esophageal squamous cell cancer (ESCC) remains poorly characterised. Here, the authors integrate multiple published datasets and systematically evaluate the mutational signatures and the related genomic and clinical features in ESCC.
- Minghao Li
- , Zicheng Zhang
- & Baosheng Li
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Article
| Open AccessSomatic whole genome dynamics of precancer in Barrett’s esophagus reveals features associated with disease progression
Barrett’s esophagus is a pre-malignant condition that can progress to esophageal cancer. Here, the authors carry out whole genome sequencing of samples from patients who did or did not progress to cancer and find that mutations in many genes occur regardless of progression status, but also find features associated with progressive disease.
- Thomas G. Paulson
- , Patricia C. Galipeau
- & Xiaohong Li
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Article
| Open AccessMulti-omic cross-sectional cohort study of pre-malignant Barrett’s esophagus reveals early structural variation and retrotransposon activity
The alterations associated with progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma are not fully characterised. Here, the authors perform a multi-omics analysis of a longitudinally-sampled BE patient cohort, identifying the impact of structural variants, including mobile elements, and the timing of molecular events during progression.
- A. C. Katz-Summercorn
- , S. Jammula
- & R. C. Fitzgerald
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Article
| Open AccessClinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2)
Patients with advanced esophageal cancer have poor prognosis and limited treatment options. This randomized, phase II trial compares the efficacy and safety of the anti-PD-1 antibody sintilimab versus chemotherapy in Chinese patients with esophageal squamous cell carcinoma after first-line therapy
- Jianming Xu
- , Yi Li
- & Christoph Mancao
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Article
| Open AccessIntegrated single-cell transcriptome analysis reveals heterogeneity of esophageal squamous cell carcinoma microenvironment
The microenvironment of oesophageal squamous cell carcinomas (ESCC) is heterogeneous and can strongly impact response to treatment. Here, the authors characterize the ESCC tumour microenvironment with single-cell RNA-seq, finding CST1 + myofibroblasts with potential biological and prognostic significance as well as immunosuppression signatures.
- Huy Q. Dinh
- , Feng Pan
- & En-Min Li
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Article
| Open AccessDissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis
Esophageal squamous-cell carcinomas (ESCC) have poor prognosis, and detailed molecular profiles are necessary to identify prognostic markers. Here the authors analyse 60 ESCC patient samples using scRNA-seq, TCR-seq and genomics; they find mucosal immunity markers associated with survival and immunosuppressive microenvironments.
- Xiannian Zhang
- , Linna Peng
- & Dongxin Lin
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Article
| Open AccessOncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis
The role of regulatory cis-elements in carcinogenesis and metastasis in esophageal squamous cell carcinoma remains crucial. Here the authors investigate H3K27ac-marked active enhancer profiles and transcriptomes in different types of esophageal tissues and identify oncogenic events and potential therapeutic targets.
- Bo Ye
- , Dandan Fan
- & Yunbo Qiao
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Article
| Open AccessInduction chemotherapy followed by definitive chemoradiotherapy versus chemoradiotherapy alone in esophageal squamous cell carcinoma: a randomized phase II trial
The benefit of induction chemotherapy before definitive chemoradiotherapy (CRT) for patients with esophageal cancer is still uncertain. The results of this phase II randomized trial show that the addition of induction chemotherapy to CRT does not improve the response rate or survival of patients with unresectable esophageal squamous cell carcinoma.
- Shiliang Liu
- , Liling Luo
- & Mian Xi
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Article
| Open AccessMulti-omics profiling of primary small cell carcinoma of the esophagus reveals RB1 disruption and additional molecular subtypes
Primary small cell carcinoma of the oesophagus has a poor prognosis, and has not been fully characterised molecularly. Here, the authors study the disease using multi-omics technology and find frequent RB1 disruptions and similarities to small cell lung cancer, opening potential therapeutic avenues.
- Renda Li
- , Zhenlin Yang
- & Jie He
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Article
| Open AccessHOXA13 in etiology and oncogenic potential of Barrett’s esophagus
Barrett’s esophagus is a pro-oncogenic lesion in the proximal gastrointestinal tract, but with a distal colon-like morphology. Here the authors report that the distal HOX gene HOXA13 is expressed in Barrett’s esophagus and in single cells of the physiological esophagus, and may underlie the phenotypic aspects of metaplasia and increase proliferation.
- Vincent T. Janmaat
- , Kateryna Nesteruk
- & Maikel P. Peppelenbosch
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Article
| Open AccessEndogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma
Volatile aldehydes can be enriched in esophageal adenocarcinoma patients’ breath. Here, the authors reveal corresponding metabolic changes in EAC tumours, which may be caused by impaired detoxification of endogenous metabolites.
- Stefan Antonowicz
- , Zsolt Bodai
- & George B. Hanna
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Article
| Open AccessGenomic and transcriptomic alterations associated with drug vulnerabilities and prognosis in adenocarcinoma at the gastroesophageal junction
Adenocarcinoma at the gastroesophageal junction has a dismal prognosis and few drug options. Here, the authors present genomic and transcriptomic features and potential therapeutic targets and prognostic biomarkers of Chinese and Caucasian tumours, and reveal the molecular similarities.
- Yuan Lin
- , Yingying Luo
- & Dongxin Lin
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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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Article
| Open AccessIdentification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma
Predicting the drug response of patients with cancer is crucial for implementing targeted therapy. Here, Su et al. make patient-derived cell lines and perform targeted sequencing and RNA-seq to identify CDKN2A/2B loss as a predictor of response to CDK4/6 inhibitors in esophageal squamous cell carcinoma.
- Dan Su
- , Dadong Zhang
- & Weimin Mao
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Article
| Open AccessGastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases
Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.
- Jiyuan An
- , Puya Gharahkhani
- & Stuart MacGregor
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Comment
| Open AccessMicroenvironment meets lineage complexity in junctional tumorigenesis
Using a sensitizing genetic model, Moon and colleagues provide compelling data for a determinant role of microenvironment in tumorigenesis, and lend support to the notion that such influences can be pharmacologically dampened to reduce the onset of cancers.
- Wa Xian
- & Frank McKeon
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Article
| Open AccessPatient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
Identifying driver genes in unstable, heterogenous tumour types can be challenging. Here, Mourikis, Benedetti, Foxall and colleagues present a machine learning algorithm to tackle this problem in esophageal adenocarcinoma.
- Thanos P. Mourikis
- , Lorena Benedetti
- & Francesca D. Ciccarelli
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Article
| Open AccessTSPAN15 interacts with BTRC to promote oesophageal squamous cell carcinoma metastasis via activating NF-κB signaling
BTRC can activate NF-κB signaling through the ubiquitination and degradation of IκB-α. Here the authors show that TSPAN15 promotes metastasis of oesophageal squamous cell cancer by enhancing BTRC induced degradation of IκB-α and subsequent activation of NF-κB.
- Baozhu Zhang
- , Zhao Zhang
- & Ying-Hui Zhu
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Article
| Open AccessEvolution of Barrett’s esophagus through space and time at single-crypt and whole-biopsy levels
Clonal dynamics of Barrett’s esophagus (BE) leading to cancer are poorly understood. Here, they report BE segments are clonal, have frequent mutations at the gastro-esophageal junction, genomic instability precedes genome doubling/clonal expansion, and a correlation between inter- and intra-biopsy genetic diversity.
- Pierre Martinez
- , Diego Mallo
- & Carlo C. Maley
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Article
| Open AccessInterplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma
Notch receptors can exert different roles in cancer. In this manuscript, the authors reveal that Notch1 activation and EMT promote tumor initiation and cancer cell heterogeneity in squamous cell carcinoma, while the repression of Notch3 by ZEB1 limits Notch1-induced differentiation, permitting Notch1-mediated EMT.
- Mitsuteru Natsuizaka
- , Kelly A. Whelan
- & Hiroshi Nakagawa
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Article
| Open AccessGenomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations
Oesophageal squamous-cell carcinoma (ESCC) is a leading cause of cancer death, and half of ESCC cases occur in China. Here, the authors provide an in depth genomic landscape for this disease and identify specific mutation signatures—one of which is linked to alcohol intake.
- Jiang Chang
- , Wenle Tan
- & Dongxin Lin
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Article
| Open AccessInhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation
Efficient therapeutic strategies to target mutant-p53 cancers are needed. Here, the authors demonstrate the molecular mechanism through which mutant-p53 tumours are susceptible to oxidative damage and propose a potential strategy for targeting such cancers by inhibiting the SLC7A11-glutathione axis.
- David S. Liu
- , Cuong P. Duong
- & Nicholas J. Clemons
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Article
| Open AccessCancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression
Cancer cells can affect cancer progression by producing systemic effects. Here, the authors show that IGF2 produced by oesophageal cancer cells increases secretion of VEGF from cancer-associated fibroblasts resulting in systemic mobilization of bone marrow-derived cells and increased metastases.
- Wen Wen Xu
- , Bin Li
- & Annie L. M. Cheung
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Article
| Open AccessRhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16
Keratin 16 is an epithelial protein highly expressed at pressure bearing sites and during wound healing and cancer. Here the authors show that K16 interacts with the inactive protease Rhbdf2, associated with Tylosis with oesophageal cancer, and that this interaction drives increased keratinocyte proliferation.
- Thiviyani Maruthappu
- , Anissa Chikh
- & David P. Kelsell
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Article
| Open AccessIntegrin α7 is a functional cancer stem cell surface marker in oesophageal squamous cell carcinoma
There is still no consensus on tumour type-specific cancer stem cell markers. Here, the authors demonstrate that ITGA7 is a potential functional marker of oesophageal cancer stem cells involved in the resistance to chemotherapy and metastasis through activation of FAK-mediated signalling.
- Xiao-Yan Ming
- , Li Fu
- & Xin-Yuan Guan
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Article
| Open AccessDifferential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy
Oesophageal adenocarcinoma is often treated with chemotherapy before surgery. Here, the authors sequence cancer samples before and after chemotherapy and examine how the genome changes, focusing on changes in driver gene mutations and differential clonal evolution between good and poor responders.
- John M. Findlay
- , Francesc Castro-Giner
- & Ian Tomlinson
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Article
| Open AccessMutational spectrum of Barrett’s stem cells suggests paths to initiation of a precancerous lesion
Barrett’s oesophagus is a precancerous intestinal metaplasia that can progress to oesophageal adenocarcinoma. In this study, the authors isolate and characterize human Barrett’s stem cells and identify a specific genomic pedigree that supports the potential role of these cells as precursors of oesophageal adenocarcinoma.
- Yusuke Yamamoto
- , Xia Wang
- & Wa Xian
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Article
| Open AccessGenomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis
Loss-of-function mutations in tumour suppressor genes are associated with oesophageal adenocarcinoma (EAC), but the mechanisms underlying EAC development remain unclear. Here, the authors show that EACs present a high frequency of genomic catastrophes resulting in amplification of potent oncogenes.
- Katia Nones
- , Nicola Waddell
- & Andrew P. Barbour
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Article |
miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma
The negative regulatory effects of phosphatases are sometimes altered in cancer, but the mechanisms that mediate this effect remain undefined. Here, the authors show that miR-508 suppresses multiple phosphatases, resulting in constitutive activation of the PI3K/Akt pathway.
- Chuyong Lin
- , Aibin Liu
- & Libing Song