Featured
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Article
| Open AccessClonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia
High hyperdiploid acute lymphoblastic leukaemia (HeH ALL) is driven by nonrandom chromosomal gains, which have been suggested to arise early - even before birth. Here, the authors use single-cell whole genome sequencing and in silico modelling to show that HeH ALL aneuploidies could originate early and follow punctuated evolution.
- Eleanor L. Woodward
- , Minjun Yang
- & Kajsa Paulsson
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Article
| Open AccessCellular mechanisms of heterogeneity in NF2-mutant schwannoma
Schwannomas are mainly caused by NF2 tumour suppressor inactivation, but they display intratumoural heterogeneity. Here the authors show that this heterogeneity is caused by the loss of polarity and acquisition of different programmes of ErbB ligand production in NF2-mutant Schwann cells.
- Christine Chiasson-MacKenzie
- , Jeremie Vitte
- & Andrea I. McClatchey
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Article
| Open AccessSpontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas
It remains unclear how spontaneous Pancreatic Ductal Adenocarcinoma (PDAC) tumors escape Yap dependency. Here, the authors show that lineage plasticity promotes spontaneous relapse following YAP ablation and reveal key transcriptional drivers that overcome YAP addiction in PDAC.
- Shigekazu Murakami
- , Shannon M. White
- & Chunling Yi
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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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Article
| Open AccessSingle-cell transcriptome profiling of the stepwise progression of head and neck cancer
Head and neck squamous cell carcinomas (HNSCCs) undergo a stepwise progression from normal tissues. In order to better understand the molecular mechanisms behind such progression, here the authors profile HNSCC tumors at different stages using single-cell RNA-seq, and observe the role of interactions with the tumor microenvironment.
- Ji-Hye Choi
- , Bok-Soon Lee
- & Chul-Ho Kim
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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 AccessMultilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer
The molecular differences between the two major gastric cancer subtypes diffuse-type gastric cancer (DGC) and intestinaltype gastric cancer (IGC) remain to be investigated. Here, integrated analysis of proteome, phospho-proteome and transcription factor activity for DGC and IGC reveals potential subtypes.
- Wenhao Shi
- , Yushen Wang
- & Chen Ding
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Article
| Open AccessGenomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer
The intermediate states of the epithelial-to-mesenchymal transition (EMT) in cancer require further molecular characterisation. Here, the authors develop a method to evaluate EMT transformation and trajectories in cancer transcriptomics data, characterising EMT macro-states, including a hybrid state, and EMT hallmarks.
- Guidantonio Malagoli Tagliazucchi
- , Anna J. Wiecek
- & Maria Secrier
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Article
| Open AccessEvolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance
It is critical to understand the factors that are associated with nasopharyngeal carcinoma (NPC) progression, metastasis and response to therapy. Here, the authors analyse primary and metastatic NPC samples using bulk and single-cell sequencing, and find two distinct evolutionary routes that lead to metastasis.
- Mei Lin
- , Xiao-Long Zhang
- & Ming-Yuan Chen
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Article
| 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 AccessPRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells
Members of the PRDI-BF1 and RIZ homology domain (PRDM) family have been involved in the regulation of several pathological conditions, including cancer. Here the authors show that PRDM1/BLIMP1 promotes immune evasion by regulating PD-L1 expression in hepatocellular carcinoma cells.
- Qing Li
- , Liren Zhang
- & Xuehao Wang
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Article
| Open AccessMultiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer
Multiregion sequencing is needed to better capture the heterogeneity of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Here, the authors analyse HCC and iCCA tumours with multiregion single-cell RNA-seq, revealing cellular dynamics and communication networks with immune cells.
- Lichun Ma
- , Sophia Heinrich
- & Xin Wei Wang
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Article
| Open AccessLY6D marks pre-existing resistant basosquamous tumor subpopulations
The identification of distinct cell populations with cellular plasticity in skin basal cell carcinoma is important for understanding treatment resistance mechanisms. Here, the authors identify the resistant LY6D+ basosquamous population that correlates with poor clinical outcomes.
- Daniel Haensel
- , Sadhana Gaddam
- & Anthony E. Oro
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Article
| Open AccessProteogenomic characterization of MiT family translocation renal cell carcinoma
The molecular landscape of microphthalmia transcription factor family translocation renal cell carcinoma tumours remain to be characterised. Here, the authors perform proteogenomic analysis and reveal dysregulation of DNA repair, mTOR signalling and metabolic processes.
- Yuanyuan Qu
- , Xiaohui Wu
- & Chen Ding
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Article
| Open AccessA framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
Nucleosome profiling from cell-free DNA (cfDNA) represents a potential approach for cancer detection and classification. Here, the authors develop Griffin, a computational framework for tumour subtype classification based on cfDNA nucleosome profiling that can work with ultra-low pass sequencing data.
- Anna-Lisa Doebley
- , Minjeong Ko
- & Gavin Ha
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Article
| Open AccessExtensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential
Epigenetic reprogramming of the androgen receptor (AR) has been identified as an important process driving prostate cancer (PCa) progression. Here, the authors analyze the role of AR chromatin binding heterogeneity in PCa clinical outcomes, metastasis and relapse.
- Jeroen Kneppers
- , Tesa M. Severson
- & Wilbert Zwart
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Article
| Open AccessBreast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis
LATS1 is reported to regulate the transition of luminal-basal-like cell plasticity in breast cancer. Here the authors report that LATS1 limits the progression of luminal breast cancer by associating with NCOR1 nuclear corepressor to repress ERα-downregulated genes in luminal cells.
- Yael Aylon
- , Noa Furth
- & Moshe Oren
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Article
| Open AccessA single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma
Studying the cell composition of acral melanoma at the single-cell level could provide some clues about its poor response to immunotherapy. Here, the authors analyse acral and cutaneous melanoma patient samples using single-cell RNA-sequencing, and reveal a severe immunosuppressive state in acral melanomas
- Chao Zhang
- , Hongru Shen
- & Jilong Yang
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Article
| Open AccessHybrid chalcogen bonds in prodrug nanoassemblies provides dual redox-responsivity in the tumor microenvironment
While homodimeric prodrug assemblies can improve drug loading and limit toxicity in cancer therapy, bioactivation within the target site is limited. Here, the authors introduce a hybrid chalcogen bond linker to a docetaxel dimeric prodrug nanoassembly and demonstrate its improved selfassembly, redox-responsivity and antitumor efficacy.
- Tian Liu
- , Lingxiao Li
- & Jin Sun
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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 AccessSingle cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis
Development of multiple myeloma is preceded by precursor conditions. Here, the authors use single cell RNA-sequencing of plasma cells from patients across disease stages to identify genomic signatures present even at the earliest stages of disease.
- Rebecca Boiarsky
- , Nicholas J. Haradhvala
- & Gad Getz
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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
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Article
| Open AccessSpatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival
Characterisation of molecular heterogeneity in glioblastoma would improve patient stratification. Here, the authors integrate spatial proteomics and clinical data from glioblastoma patients and identify 3 molecular groups and a 5-protein signature that was associated with survival.
- Marie Duhamel
- , Lauranne Drelich
- & Michel Salzet
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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
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Article
| Open AccessElucidating tumor heterogeneity from spatially resolved transcriptomics data by multi-view graph collaborative learning
Multi-view graph approaches could enhance the analysis of tissue heterogeneity in spatial transcriptomics. Here, the authors develop the Spatial Transcriptomics data analysis by Multiple View Collaborative-learning - stMVC - framework, and apply it to detect spatial domains and cell states in brain and tumor tissues.
- Chunman Zuo
- , Yijian Zhang
- & Luonan Chen
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Article
| Open AccessSpatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones
Spatial heterogeneity in prostate cancer can contribute to its resistance to androgen deprivation therapy (ADT). Here, the authors analyse prostate cancer samples before and after ADT using Spatial Transcriptomics, and find heterogeneous pre-treatment tumour cell populations and stromal cells that are associated with resistance.
- Maja Marklund
- , Niklas Schultz
- & Joakim Lundeberg
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Article
| Open AccessTraject3d allows label-free identification of distinct co-occurring phenotypes within 3D culture by live imaging
There are currently a lack of tools to detect heterogeneity in 3D cultures. Here the authors report Traject3d as a framework to identify heterogeneous states in 3D culture and to understand how these give rise to distinct phenotypes using label-free multi-day time-lapse imaging.
- Eva C. Freckmann
- , Emma Sandilands
- & David M. Bryant
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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
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Article
| Open AccessSingle-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids
The mechanisms of tumor heterogeneity in pediatric hepatoblastoma remain poorly characterized. Here, the authors perform single cell RNA sequencing and identify 5 signatures with distinct responses to chemotherapy using patient-derived hepatoblastoma spheroid cultures.
- Hanbing Song
- , Simon Bucher
- & Bruce Wang
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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
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Article
| Open AccessClonal diversification and histogenesis of malignant germ cell tumours
The molecular characterisation of germ cell tumours (GCT) is necessary to understand their development and histological diversification. Here, the authors use whole-genome and transcriptome sequencing of GCTs across distinct histologies to reveal their somatic evolution and clonal diversification, as well as identify several putative biomarkers for treatment stratification.
- Thomas R. W. Oliver
- , Lia Chappell
- & Sam Behjati
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Article
| Open AccessAccurate determination of CRISPR-mediated gene fitness in transplantable tumours
Gene fitness and essentiality analyses using in vivo cancer models are challenging due to multiple confounders. Here, the authors develop a quantitative approach to study CRISPR-transduced patient-derived xenografts, which they use to analyse in vivo gene fitness in breast cancers and the biological features that influence uncertainty in fitness estimation.
- Peter Eirew
- , Ciara O’Flanagan
- & Samuel Aparicio
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Article
| Open AccessThe spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states
Spatially and temporally resolved data can improve our understanding of evolution and treatment resistance in multiple myeloma (MM). Here, the authors analyse spatial and longitudinal heterogeneity in MM patients using multi-region sequencing, and identify subclones associated with relapse and therapy resistance.
- Leo Rasche
- , Carolina Schinke
- & Niels Weinhold
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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
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Article
| Open AccessClonal barcoding with qPCR detection enables live cell functional analyses for cancer research
DNA barcoding methods for the analysis of clonal heterogeneity in cancer have been limited in terms of throughput and practical requirements. Here, the authors develop SunCatcher, a rapid and sensitive barcoding approach for live single-cell clonal evolution analysis, and use this method to study breast cancer cell populations.
- Qiuchen Guo
- , Milos Spasic
- & Sandra S. McAllister
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Article
| Open AccessOccult polyclonality of preclinical pancreatic cancer models drives in vitro evolution
It is unclear if the molecular profiles of pancreatic ductal adenocarcinoma (PDAC) preclinical models remain stable during propagation. Here, the authors characterise clonal evolution throughout propagation in PDAC cell lines and a patient-derived organoid using single-cell genomics, transcriptomics and epigenomics.
- Maria E. Monberg
- , Heather Geiger
- & Anirban Maitra
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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
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Article
| Open AccessClinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets
Sarcomas are rare tumours with many different subtypes and clinical outcomes; a broader knowledge of their genetic features is required. Here, the authors analyse 2138 soft tissue and bone sarcomas across 45 subtypes using MSK-IMPACT targeted sequencing and find genomic groups that are distinct from histological subgroups.
- Benjamin A. Nacev
- , Francisco Sanchez-Vega
- & William D. Tap
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Article
| Open AccessClinical genomic profiling in the management of patients with soft tissue and bone sarcoma
Comprehensive molecular profiles are required to understand and treat sarcomas, which comprise more than 70 different subtypes. Here, the authors profile the genomic landscape of 7494 sarcomas across 44 histologies using targeted panel sequencing and identify potential therapeutic targets.
- Mrinal M. Gounder
- , Narasimhan P. Agaram
- & Dexter X. Jin
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Article
| Open AccessPersister state-directed transitioning and vulnerability in melanoma
Slow-cycling melanoma persister cells are characterised by a high, reversible expression of H3K4 demethylase KDM5B. Here, the authors use genetic and chemical methods to enforce a permanent high expression of KDM5B and show that these cells transit to a melanocytic differentiated state and undergo cell cycle arrest.
- Heike Chauvistré
- , Batool Shannan
- & Alexander Roesch
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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
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Article
| Open AccessA conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs
Notch signaling is known to control neuroendocrine fate in the lungs. Shue and colleagues further identify the REST and YAP transcriptional regulators as key components of the Notch signaling pathway in the control of the neuroendocrine cell fate in lung development, lung injury response, and small-cell lung cancer.
- Yan Ting Shue
- , Alexandros P. Drainas
- & Julien Sage
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Article
| Open AccessIntegrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages
Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated tumours and lacked information about the phosphoproteome. Here, the authors present a comprehensive HCC proteogenomics and phosphoproteomics study in patient samples from multiple etiologies and stages.
- Charlotte K. Y. Ng
- , Eva Dazert
- & Markus H. Heim
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Article
| Open AccessComprehensive profiling of 1015 patients’ exomes reveals genomic-clinical associations in colorectal cancer
The ChangKang (Heathy Bowel) project was established to collect molecular and clinical information of a thousand Chinese colorectal cancer patients. Here, the authors present the genomic landscape of the ChangKang cohort and find a subgroup of patients defined by abnormal mitochondrial copy numbers.
- Qi Zhao
- , Feng Wang
- & Rui-Hua Xu
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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 AccessA proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population
Clear cell renal cell carcinoma is an aggressive form of renal cancer, with differences in genomic mutations reported between Western and Eastern populations. In this study, the authors have compiled proteogenomic analysis of Chinese ccRCC to reveal genomic alterations and dysregulation of immune and metabolic responses.
- Yuanyuan Qu
- , Jinwen Feng
- & Chen Ding
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Article
| Open AccessA single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response
The impact of tumour heterogeneity on drug response in breast cancer is not fully understood. Here, the authors characterise cell lines from all main breast cancer subtypes using single-cell RNA-seq and train a deconvolution algorithm to predict drug responses in heterogeneous tumour cell populations.
- G. Gambardella
- , G. Viscido
- & D. di Bernardo
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Article
| Open AccessSingle-cell transcriptomic analysis suggests two molecularly distinct subtypes of intrahepatic cholangiocarcinoma
The molecular classification and tumour microenvironment in intrahepatic cholangiocarcinoma (iCCA) need further characterisation. Here, the authors perform single cell RNA-sequencing from 14 pairs of iCCA tumours and non-tumour liver tissues and propose S100P and SPP1 as markers for patient classification.
- Guohe Song
- , Yang Shi
- & Qiang Gao