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| Open AccessThe SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression
Tumor cell-microenvironment interactions generate heterogeneity and promote progression. Here, Ma et al. show that the E3 ligase SIAH2 degrades NRF1 in response to hypoxia to enhance pro-tumor metabolic and environmental effects, whereas NRF1 stabilization sensitizes tumor cells to apoptosis.
- Biao Ma
- , Hongcheng Cheng
- & Quan Chen
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Article
| Open AccessCounting growth factors in single cells with infrared quantum dots to measure discrete stimulation distributions
Measuring growth factors in single cells at physiologically relevant stimulation doses is challenging. Here the authors use fluorescent quantum dots and calibrated three-dimensional deconvolution microscopy to digitally count growth factors in single cells and reveal stimulation distributions in cancer cells.
- Phuong Le
- , Sung Jun Lim
- & Andrew M. Smith
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Article
| Open AccessBarcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer
Triple negative breast cancers (TNBC) disseminate and metastasise, but the clonal relationship of metastases to primary tumours is poorly understood. Here, the authors use cellular barcoding of TNBC patient-derived xenografts and track the fate of barcoded clones in primary tumours and their metastases, including after resection or chemotherapy.
- D. Merino
- , T. S. Weber
- & S. H. Naik
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Article
| Open AccessExploring the landscape of focal amplifications in cancer using AmpliconArchitect
Focal amplifications are prevalent in many cancer genomes. Here, the authors present AmpliconArchitect (AA), a computational tool for reconstructing their architecture, and reveal an extrachromosomal origin for focal amplifications, including hybrid human-virus elements in HPV-mediated cancers.
- Viraj Deshpande
- , Jens Luebeck
- & Vineet Bafna
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Article
| Open AccessLocal mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer
Intratumoral immunity heterogeneity is poorly characterized. Here the authors apply exome sequencing, transcriptome profiling and T-cell repertoire profiling to multiple loci of non-small-cell lung cancer patients' biopsies and find high spatial immune heterogeneity with local mutational burden correlating with T-cell clonal expansion but not with cytotoxicity.
- Qingzhu Jia
- , Wei Wu
- & Bo Zhu
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Article
| Open AccessSingle-cell mutation identification via phylogenetic inference
Cross-cell heterogeneity of genotypes can be revealed by analyzing single-cell sequencing data. Here the authors develop a tool for single-cell variant calling via phylogenetic inference, and use it to analyze cancer genomics datasets.
- Jochen Singer
- , Jack Kuipers
- & Niko Beerenwinkel
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Article
| Open AccessHigh-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer
It is unclear how intra-tumoral heterogeneity contributes to metastasis. Here the authors study the clonal dynamics of triple negative breast cancer metastasis using patient derived xenografts and demonstrate that primary tumor clones harbor properties that support seeding and colonization of multiple organs.
- Gloria V. Echeverria
- , Emily Powell
- & Helen Piwnica-Worms
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| Open AccessLongitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy
Drug resistance is one of the major causes of cancer-related deaths. Here, the authors using single cell RNA-seq of oral squamous cell carcinoma patient samples pre- and post-cisplatin treatment show that phenotypically homogenous cell populations display cell state plasticity, with poised chromatin marks at mesenchymal genes in epithelial cells, and that the loss of stem factor Sox2 but gain of Sox9 expression (with de novo gain of H3K27ac sites) is associated with drug-induced adaptation.
- Ankur Sharma
- , Elaine Yiqun Cao
- & Ramanuj DasGupta
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Article
| Open AccessSingle-cell barcode analysis provides a rapid readout of cellular signaling pathways in clinical specimens
Diagnostic tests need optimization to avoid invasive and costly repeated biopsies. Here the authors present an antibody-DNA barcoding approach where harvested single cells can be re-stained through custom oligonucleotide-fluorophore conjugates, enabling multiplexed analysis of cancer pathways.
- Randy J. Giedt
- , Divya Pathania
- & Ralph Weissleder
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Article
| Open AccessLinking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses
The functional significance of the observed heterogeneity of androgen receptor (AR) expression in prostate cancer is unknown. Here the authors show AR expression heterogeneity is associated with distinct castration/enzalutamide responses and identify BCL-2 as a potential therapeutic target in castration-resistant prostate cancer.
- Qiuhui Li
- , Qu Deng
- & Dean G. Tang
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Article
| Open AccessUnravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq
Triple-negative breast cancer is highly heterogeneous and aggressive. Here, the authors utilise single-cell RNA sequencing to investigate this heterogeneity, and discover a subpopulation of cells associated with metastasis and treatment resistance signatures, and linked to long term survival outcomes.
- Mihriban Karaayvaz
- , Simona Cristea
- & Leif W. Ellisen
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Article
| Open AccessCirculating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer
Small cell lung cancer (SCLC) may evolve under treatment. But tumor tissues are often not available to study evolution of SCLC. Here, the authors utilize circulating tumor DNA to investigate the genomic evolution and subclonal architecture of SCLC during therapy.
- Jingying Nong
- , Yuhua Gong
- & Jinghui Wang
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Article
| Open AccessA temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer
Advanced colorectal cancers are characterised by intra-tumour heterogeneity dictated by neutral evolution. Here the authors analyse early colorectal tumours by whole-exome sequencing and find that Darwinian evolution determines the fate of early lesions in colorectal adenoma and carcinoma in situ.
- Tomoko Saito
- , Atsushi Niida
- & Koshi Mimori
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Article
| Open AccessSpatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity
Heterogeneity within tumors presents a challenge to cancer treatment. Here, the authors investigate transcriptional heterogeneity in prostate cancer, examining expression profiles of different tissue components and highlighting expression gradients in the tumor microenvironment.
- Emelie Berglund
- , Jonas Maaskola
- & Joakim Lundeberg
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Article
| Open AccessReliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies
The emergence of sub-clones that are resistant to targeted agents is a major therapeutic obstacle in oncology. Here, using colorectal cancer as a model system, the authors show that interfering with ancestral oncogenic events present in all subclones-like APC-WNT pathway alterations—can restrain the emergence of drug-resistant populations.
- Mariangela Russo
- , Simona Lamba
- & Alberto Bardelli
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Article
| Open AccessmiR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
Cancer-associated fibroblasts (CAFs) are an important part of the tumor microenvironment. Here the authors characterize four subsets of CAFs across human samples of ovarian cancer subtypes and show in the mesenchymal subtype a specific CAF-S1 population that attracts immunosuppressive Tregs via CXCL12β.
- Anne-Marie Givel
- , Yann Kieffer
- & Fatima Mechta-Grigoriou
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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 AccessMutational patterns in chemotherapy resistant muscle-invasive bladder cancer
The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.
- David Liu
- , Philip Abbosh
- & Eliezer M. Van Allen
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Article
| Open AccessRobust RNA-based in situ mutation detection delineates colorectal cancer subclonal evolution
Methods that analyze intra-tumor genetic heterogeneity often do not preserve the spatial context of tumor subclones. Here, the authors present BaseScope, a mutation-specific RNA in situ hybridization assay and spatially map colorectal cancer and adenoma KRAS, BRAF and PIK3CA driver gene mutant subclones.
- Ann-Marie Baker
- , Weini Huang
- & Trevor A. Graham
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Article
| Open AccessNovel peptide probes to assess the tensional state of fibronectin fibers in cancer
The extracellular matrix is under variable strain, but we lack the tools to detect differences in strain. Here the authors develop a probe based on a bacterial fibronectin-binding peptide that binds to relaxed fibronectin fibrils and detects relaxed matrix in cell culture, tissue slices and in vivo.
- Simon Arnoldini
- , Alessandra Moscaroli
- & Viola Vogel
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Article
| Open AccessMYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance
Neuroendocrine differentiation of epithelial tumor cells can contribute to cancer cell resistance and survival. Here, the authors show that dysregulated c-Myc promotes neuroendocrine differentiation in pancreatic ductal adenocarcinoma, leading to poor survival and chemoresistance.
- Amy S. Farrell
- , Meghan Morrison Joly
- & Rosalie C. Sears
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Article
| Open AccessCombating subclonal evolution of resistant cancer phenotypes
In metastatic breast cancer, subclonal evolution can drive drug resistance. Here, the authors genetically and transcriptionally follow the evolution of four breast cancers over time and treatment, and suggest a phenotype-targeted treatment strategy to adapt to cancer as it evolves.
- Samuel W. Brady
- , Jasmine A. McQuerry
- & Andrea H. Bild
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Article
| Open AccessSimultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer
Across cancer types tumor heterogeneity has been observed, but how this relates to tumor evolution is unclear. Here, the authors sequence multiple synchronous lung cancers, highlighting the evolutionary pressures that simultaneously shape the expansion and constraint of genomic heterogeneity.
- Pengfei Ma
- , Yujie Fu
- & Guanglei Zhuang
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Article
| Open AccessTumor-associated B-cells induce tumor heterogeneity and therapy resistance
Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.
- Rajasekharan Somasundaram
- , Gao Zhang
- & Stephan N. Wagner
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Article
| Open AccessCheckpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8+ T cells
Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen-specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations.
- M. Fehlings
- , Y. Simoni
- & E. W. Newell
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Article
| Open AccessEMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells
Recent findings have challenged the centrality of epithelial-to-mesenchymal transition (EMT) in promoting tumour progression. Here the authors show that EMT cells can promote breast cancer metastasis by non-cell autonomous activation of the GLI transcriptional program in neighbouring epithelial tumour cells.
- Deepika Neelakantan
- , Hengbo Zhou
- & Heide L. Ford
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Article
| Open AccessImage-guided genomics of phenotypically heterogeneous populations reveals vascular signalling during symbiotic collective cancer invasion
The mechanisms linking phenotypic heterogeneity to collective cancer invasion are unclear. Here the authors develop an image-guided genomic technique to select and amplify leader and follower cells fromin vitroinvading cell packs and find a cooperative symbiotic relationship between these two cell populations.
- J. Konen
- , E. Summerbell
- & A. I. Marcus
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Article
| Open AccessSingle-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer
Genetic heterogeneity in breast cancer has been demonstrated at a single-cell resolution with high levels of genome coverage. Here, the authors perform transcriptome analysis of 515 single cells from 11 patients and define core gene expression signatures for subtype-specific single breast cancer cells and tumour-infiltrating immune cells.
- Woosung Chung
- , Hye Hyeon Eum
- & Woong-Yang Park
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Article
| Open AccessHierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations
To limit the accumulation of somatic mutations, renewing tissues must minimize the number of times each cell divides during differentiation. Here, the authors analytically derive the lower limit of lifetime divisional load of a tissue, show that hierarchically differentiating tissues can approach this limit, and that this depends on uneven divisional rates across the hierarchy.
- Imre Derényi
- & Gergely J. Szöllősi
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Article
| Open AccessDNA copy number changes define spatial patterns of heterogeneity in colorectal cancer
The contribution of intra-tumour heterogeneity is increasingly associated with resistance to therapy. Here, the authors use genomic analyses to study heterogeneity in colorectal cancer and perform in-depth reconstruction of heterogeneity in one sample.
- Soulafa Mamlouk
- , Liam Harold Childs
- & Christine Sers
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Article
| Open AccessGenomic heterogeneity of multiple synchronous lung cancer
Some patients present with multiple lung tumours but it is unclear whether these are metastases or individual lesions. Here, the authors use genomics techniques to demonstrate in six patients that multiple tumours have individual genetic profiles and represent separate tumours.
- Yu Liu
- , Jianjun Zhang
- & Yanning Gao
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Article
| Open AccessAromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers
Aromatase inhibitors are used to treat oestrogen-receptor-positive breast cancer. Here, the authors use genomic approaches to analyse tumours before and after neo-adjuvant treatment and find that treatment alters the clonal landscape of the tumours.
- Christopher A. Miller
- , Yevgeniy Gindin
- & Matthew J. Ellis
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| Open AccessPatients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes
Some individuals present with multiple synchronous colorectal tumours, but the genetic understanding of this is unclear. Here, the authors use a sequencing strategy to show that the synchronous tumours are genetically independent and the patients harbour rare germline damaging mutations in genes associated with the immune system.
- Matteo Cereda
- , Gennaro Gambardella
- & Francesca D. Ciccarelli
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Article
| Open AccessSpatial niche formation but not malignant progression is a driving force for intratumoural heterogeneity
It has been increasingly recognised that tumours are not made up of a homogeneous population of cells. Here, the authors show heterogeneous expression of five protein markers in renal cell cancer and demonstrate that the progression of the tumour does not influence the degree of heterogeneity in the tumour.
- Rouven Hoefflin
- , Bernd Lahrmann
- & Stefan Duensing
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Article
| Open AccessCirculating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients
EGFR-mutant non-small cell lung cancer is routinely treated with EGFR inhibitors, although resistance inevitably develops. Here, the authors sequence circulating tumour DNA and show that resistance to the third-generation inhibitor rociletinib is heterogeneous and recurrently involves somatic alterations of MET, EGFR, PIK3CA, ERRB2, and KRAS.
- Jacob J. Chabon
- , Andrew D. Simmons
- & Maximilian Diehn
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Article
| Open AccessHighly variable cancer subpopulations that exhibit enhanced transcriptome variability and metastatic fitness
Phenotypic and genetic intra-tumor heterogeneity have an important role in cancer progression and therapeutic resistance. Here, the authors show that phenotypically variable tumor subpopulations exhibit higher metastatic potential and display enhanced intra-clonal transcriptomic variability, likely promoted by deregulated spliceosome activity.
- Alexander Nguyen
- , Mitsukuni Yoshida
- & Sohail F. Tavazoie
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Article
| Open AccessImaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish
Direct visualisation of heterogeneous cell populations in live animals has been challenging. Here, the authors optimize cell transplantation into optically clear immune-deficient zebrafish, and use intravital imaging to track and to assess functional diversity of individual cancer cells in vivo.
- Qin Tang
- , John C. Moore
- & David M. Langenau
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Article
| Open AccessPredicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity
Efficacy of anticancer treatments vary across patients, imposing a need for personalized approaches. Here the authors show that responsiveness to chemotherapy can be predicted using tumour explant cultures in a patient-matched microenvironment, coupled with a machine-learning algorithm.
- Biswanath Majumder
- , Ulaganathan Baraneedharan
- & Pradip K. Majumder
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Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity
Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma displaying biliary phenotypes are aggressive cancers. Fujimoto et al. characterize the mutational profile of chronic hepatitis and identify mutations in KRAS and IDHassociated with poor survival.
- Akihiro Fujimoto
- , Mayuko Furuta
- & Hidewaki Nakagawa
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Reliable detection of subclonal single-nucleotide variants in tumour cell populations
The detection of subclonal variants in heterogeneous cancer specimens is a challenge due to errors that occur during sequencing. In this study, a statistical algorithm and a sequencing strategy are reported that circumvent this issue and can accurately detect variants at a frequency as low as 1/10,000.
- Moritz Gerstung
- , Christian Beisel
- & Niko Beerenwinkel