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| Open AccessNetrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer
We describe netrin-1 upregulation in a majority of human endometrial carcinomas and demonstrate that netrin-1 blockade, using the anti-netrin-1 antibody NP137, is effective both in a mouse model and in patients with endometrial carcinomas.
- Philippe A. Cassier
- , Raul Navaridas
- & Patrick Mehlen
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Pharmacological targeting of netrin-1 inhibits EMT in cancer
Netrin-1 is upregulated in cancer models that undergo spontaneous epithelial-to-mesenchymal transition, and its targeting blocks the progression of tumour cells to a late mesenchymal state, suggesting possible therapeutic applications.
- Justine Lengrand
- , Ievgenia Pastushenko
- & Cédric Blanpain
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Article
| Open AccessHeritable transcriptional defects from aberrations of nuclear architecture
Micronuclei, which are common features of nuclei in cancer cells, can generate heritable sources of transcriptional suppression, a finding that establishes an inherent relationship between chromosomal instability and variation in chromatin state and gene expression.
- Stamatis Papathanasiou
- , Nikos A. Mynhier
- & David Pellman
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Article
| Open AccessEpigenetic dysregulation from chromosomal transit in micronuclei
Missegregated chromosomes that are sequestrated in micronuclei are subject to changes in histone modifications leading to abnormalities in chromatin accessibility that remain long after the chromosomes have been reincorporated into the primary nucleus.
- Albert S. Agustinus
- , Duaa Al-Rawi
- & Samuel F. Bakhoum
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Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours
A study identifies 41 consensus gene expression meta-programs that are coordinately upregulated in subpopulations of malignant cells across tumour types, providing a comprehensive picture of hallmarks of intratumour heterogeneity.
- Avishai Gavish
- , Michael Tyler
- & Itay Tirosh
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Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA
Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.
- Christopher Abbosh
- , Alexander M. Frankell
- & Charles Swanton
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Article
| Open AccessGenomic–transcriptomic evolution in lung cancer and metastasis
Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.
- Carlos Martínez-Ruiz
- , James R. M. Black
- & Nicholas McGranahan
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Article
| Open AccessRHOJ controls EMT-associated resistance to chemotherapy
RHOJ regulates epithelial-to-mesenchymal-transition-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy.
- Maud Debaugnies
- , Sara Rodríguez-Acebes
- & Cédric Blanpain
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| Open AccessMicrobiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer
Indole-3-acetic acid (3-IAA), a tryptophan metabolite derived from the gut microbiota, is associated with a better response to chemotherapy in pancreatic ductal adenocarcinoma (PDAC), and dietary interventions could have a role in the treatment of PDAC.
- Joseph Tintelnot
- , Yang Xu
- & Nicola Gagliani
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| Open AccessEffect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer
Spatial profiling and single-cell RNA sequencing are used to map the spatial distribution of the microbiota within human tumours, revealing how intratumoral microbial communities contribute to tumour heterogeneity and cancer progression.
- Jorge Luis Galeano Niño
- , Hanrui Wu
- & Susan Bullman
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Article
| Open AccessSingle-cell genomic variation induced by mutational processes in cancer
Single-cell whole-genome sequencing shows that 'foreground' cell-to-cell structural variation and alterations in copy number are associated with genomic diversity and evolution in triple-negative breast and high-grade serous ovarian cancers.
- Tyler Funnell
- , Ciara H. O’Flanagan
- & Samuel Aparicio
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| Open AccessThe co-evolution of the genome and epigenome in colorectal cancer
A study maps genetic and epigenetic heterogeneity of primary colorectal adenomas and cancers at single-clone resolution through spatial multi-omic profiling of individual glands and adjacent normal tissue.
- Timon Heide
- , Jacob Househam
- & Andrea Sottoriva
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| Open AccessPhenotypic plasticity and genetic control in colorectal cancer evolution
Intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer, with most genetic intratumour variation having no detected phenotypic consequence and transcriptional plasticity being widespread within a tumour.
- Jacob Househam
- , Timon Heide
- & Trevor A. Graham
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Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer
Deep whole-genome sequencing of serial blood samples and matched metastatic tissue reveals that circulating tumour DNA profiling enables detailed study of treatment-driven subclone dynamics, epigenomics and genome-wide somatic evolution in metastatic human cancers.
- Cameron Herberts
- , Matti Annala
- & Alexander W. Wyatt
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GREM1 is required to maintain cellular heterogeneity in pancreatic cancer
The BMP inhibitor GREM1 is a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse.
- Linxiang Lan
- , Theodore Evan
- & Axel Behrens
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Non-genetic determinants of malignant clonal fitness at single-cell resolution
Non-genetic malignant clonal dominance is a cell-intrinsic and heritable property that underpins clonal output and response to therapy in cancer.
- Katie A. Fennell
- , Dane Vassiliadis
- & Mark A. Dawson
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ecDNA hubs drive cooperative intermolecular oncogene expression
Extrachromosomal DNA (ecDNA) congregates in clusters called ecDNA hubs that promote intermolecular interactions between gene-regulatory regions and thereby amplify the expression of oncogenes such as MYC in cancer cell lines.
- King L. Hung
- , Kathryn E. Yost
- & Howard Y. Chang
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Dietary palmitic acid promotes a prometastatic memory via Schwann cells
Palmitic acid induces stable transcriptional and chromatin changes that lead to long-term stimulation of metastasis in orthotopic models of cancer through the secretion by tumour-associated Schwann cells of a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation.
- Gloria Pascual
- , Diana Domínguez
- & Salvador Aznar Benitah
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Breast tumours maintain a reservoir of subclonal diversity during expansion
Single-cell analysis of genomes from primary human breast tumours and cell lines shows that chromosomal aberrations continue to evolve during primary tumour expansion, resulting in a milieu of subclones within the tumour.
- Darlan C. Minussi
- , Michael D. Nicholson
- & Nicholas E. Navin
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Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis
In mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, malignant progression and metastasis through the activation of a hybrid epithelial-to-mesenchymal transition phenotype.
- Ievgenia Pastushenko
- , Federico Mauri
- & Cédric Blanpain
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Single-cell mutation analysis of clonal evolution in myeloid malignancies
The evolution of myeloid malignancies is investigated using combined single-cell sequencing and immunophenotypic analysis.
- Linde A. Miles
- , Robert L. Bowman
- & Ross L. Levine
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Functional genomic landscape of cancer-intrinsic evasion of killing by T cells
Genome-wide CRISPR screens in mouse cancer cell lines are used to identify a core, conserved set of genes and pathways that govern how cancer cells evade killing by cytotoxic T lymphocytes.
- Keith A. Lawson
- , Cristovão M. Sousa
- & Jason Moffat
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Pervasive lesion segregation shapes cancer genome evolution
Mutagenic lesions such as those that give rise to cancer frequently segregate—unrepaired—during cell division, resulting in phasing of multiple alleles across generations of daughter cells and consequent tumour heterogeneity.
- Sarah J. Aitken
- , Craig J. Anderson
- & Martin S. Taylor
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The single-cell pathology landscape of breast cancer
A single-cell, spatially resolved analysis of breast cancer demonstrates the heterogeneity of tumour and stroma tissue and provides a more-detailed method of patient classification than the current histology-based system.
- Hartland W. Jackson
- , Jana R. Fischer
- & Bernd Bodenmiller
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Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition
Populations of KRAS(G12C)-mutant cancer cells can rapidly bypass the effects of treatment with KRAS(G12C) inhibitors because a subset of cells escapes drug-induced quiescence by producing new KRAS(G12C) that is maintained in its active, drug-insensitive state.
- Jenny Y. Xue
- , Yulei Zhao
- & Piro Lito
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Neoantigen-directed immune escape in lung cancer evolution
RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.
- Rachel Rosenthal
- , Elizabeth Larose Cadieux
- & Andrew Kidd
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Precancerous neoplastic cells can move through the pancreatic ductal system
Comparison of multiple lesions from individual pancreases sheds light on how ancestral clones can spread through the ductal system and give rise to precursor lesions, with acquisition of further mutations leading to pancreatic cancer.
- Alvin P. Makohon-Moore
- , Karen Matsukuma
- & Christine A. Iacobuzio-Donahue
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Identification of the tumour transition states occurring during EMT
Epithelial-to-mesenchymal transition in tumour cells occurs through distinct intermediate states, associated with different metastatic potential, cellular properties, gene expression, and chromatin landscape
- Ievgenia Pastushenko
- , Audrey Brisebarre
- & Cédric Blanpain
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Intra-tumour diversification in colorectal cancer at the single-cell level
Organoids derived from individual cells from colorectal cancers and adjacent normal tissue are used to investigate intra-tumour diversification at the genomic, epigenetic and functional levels.
- Sophie F. Roerink
- , Nobuo Sasaki
- & Hans Clevers
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Chromosomal instability drives metastasis through a cytosolic DNA response
In chromosomally unstable tumour cells, rupture of micronuclei exposes genomic DNA and activates the cGAS–STING cytosolic DNA-sensing pathway, thereby promoting metastasis.
- Samuel F. Bakhoum
- , Bryan Ngo
- & Lewis C. Cantley
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A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma
A subset of Kras and p53 mutant cancer cells acts as a Wnt-producing niche for another cancer cell subset, and porcupine inhibition disrupts Wnt secretion in this niche, thereby suppressing proliferative potential and leading to therapeutic benefit.
- Tuomas Tammela
- , Francisco J. Sanchez-Rivera
- & Tyler Jacks
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Letter |
Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer
In a mouse model of small-cell lung cancer and in human tumours, activation of the Notch pathway can lead to a cell fate switch of neuroendocrine cells to less proliferative non-neuroendocrine cells, generating intratumoural heterogeneity.
- Jing Shan Lim
- , Alvaro Ibaseta
- & Julien Sage
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Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution
Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.
- Christopher Abbosh
- , Nicolai J. Birkbak
- & Charles Swanton
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Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells
The first formal evidence of the shared and independent ability of basal cells and luminal pro-genitors isolated from normal human mammary tissue and transduced with a single oncogene to initiate tumorigeneses when introduced into mice.
- Long V. Nguyen
- , Davide Pellacani
- & Connie J. Eaves
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A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity
A new model of tumour evolution is presented to explain how short-range migration and cell turnover within the tumour can provide the basic environment of rapid cell mixing, allowing even a small selective advantage to dominate the mass within relevant time frames.
- Bartlomiej Waclaw
- , Ivana Bozic
- & Martin A. Nowak
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Letter |
Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity
PIK3CA mutations are associated with distinct types of human breast cancers but the cellular origin and mechanisms responsible for this heterogeneity were unclear; here, using a genetic approach in mice, PIK3CA mutations are shown to activate a genetic program directing multiple cell fates in normally lineage-restricted cell types.
- Alexandra Van Keymeulen
- , May Yin Lee
- & Cédric Blanpain
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Letter |
The evolutionary history of lethal metastatic prostate cancer
The subclonal composition of human prostate tumours and their metastases has been mapped by whole-genome sequencing, thus establishing the evolutionary trees behind the development and spread of these cancers; an important observation was that metastases could be re-seeded multiple times, and spread from one tumour to another was frequently seen.
- Gunes Gundem
- , Peter Van Loo
- & G. Steven Bova
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Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity
To investigate the role of sub-clonal tumour heterogeneity in cancer progression, a mouse xenograft model was used which revealed that tumour growth can be driven by a minor cell subpopulation by a non-cell-autonomous mechanism, although this minor subpopulation can be outcompeted by faster proliferating competitors.
- Andriy Marusyk
- , Doris P. Tabassum
- & Kornelia Polyak
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Letter |
Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers
In a mouse model of tumours initiated by Wnt signalling in which a proportion of tumours are biclonal, that is, composed of basal and luminal clones with distinct genetic alterations, these clones are shown to cooperate to maintain tumour growth in a Wnt-dependent manner.
- Allison S. Cleary
- , Travis L. Leonard
- & Edward J. Gunther
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Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia
The authors identify pre-leukaemic haematopoietic stem cells (HSCs) in patients with acute myeloid leukaemia; these pre-leukaemic HSCs have the capacity of normal multi-lineage haematopoietic differentiation with a competitive growth advantage over wild-type HSCs, and owing to their persistence may serve as a reservoir for therapeutic resistance and relapse.
- Liran I. Shlush
- , Sasan Zandi
- & John E. Dick
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Outlook |
Stem cells: Bad seeds
Leukaemia treatments must eliminate the versatile cells that can bring the cancer back to life years later.
- Cassandra Willyard
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Outlook |
Cell banks: Life blood
Stem cells from the umbilical cord are among the latest weapons in the fight against leukaemia.
- Melinda Wenner Moyer
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Outlook |
Genetics: Written in blood
Technologies that rapidly sequence DNA reveal deep genetic diversity both within and among individuals with leukaemia.
- Sarah DeWeerdt
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Letter |
GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas
Atypical protein kinase C ι/λ is shown to be critical, through its regulation of the transcription factor GLI, for hedgehog-dependent processes, such as the growth of basal cell carcinomas.
- Scott X. Atwood
- , Mischa Li
- & Anthony E. Oro
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Letter |
Defining the mode of tumour growth by clonal analysis
Using genetic lineage tracing, tumour cells are traced in vivo in an unperturbed solid tumour; in a carcinogen-induced papilloma mouse model, cells in these benign lesions are found to mirror the clonal hierarchy organization of normal tissue.
- Gregory Driessens
- , Benjamin Beck
- & Cédric Blanpain