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Article
| Open AccessSpatially resolved clonal copy number alterations in benign and malignant tissue
Copy number variations inferred from spatial transcriptomics data in benign and malignant tissue reveal clonal architecture at the organ-wide level.
- Andrew Erickson
- , Mengxiao He
- & Joakim Lundeberg
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Article
| Open AccessBrown-fat-mediated tumour suppression by cold-altered global metabolism
Mild cold exposure activates a substantial amount of brown adipose tissue (BAT) in a patient with cancer, reducing tumour-associated glucose uptake, and activation of BAT in mice inhibits the growth of tumours by decreasing blood glucose and impeding glycolysis-based metabolism in cancer cells.
- Takahiro Seki
- , Yunlong Yang
- & Yihai Cao
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Article
| Open AccessPI3K drives the de novo synthesis of coenzyme A from vitamin B5
The PI3K–PANK4 axis regulates coenzyme A synthesis, the abundance of acetyl-CoA, and CoA-dependent processes such as lipid metabolism, and these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone and growth-factor-driven or oncogene-driven metabolism and growth.
- Christian C. Dibble
- , Samuel A. Barritt
- & Alex Toker
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Article |
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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Article
| Open AccessMechanisms of APOBEC3 mutagenesis in human cancer cells
Endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells, and APOBEC3A is the main driver of these mutations.
- Mia Petljak
- , Alexandra Dananberg
- & John Maciejowski
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Article |
Structure–function analysis of the SHOC2–MRAS–PP1C holophosphatase complex
- Jason J. Kwon
- , Behnoush Hajian
- & Andrew J. Aguirre
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Review Article |
Inflammatory memory and tissue adaptation in sickness and in health
A Review on inflammatory memory in non-immune cells of different epithelia and neurons, and the potential mechanisms controlling these epigenetic memories and their implications in human health and disease.
- Shruti Naik
- & Elaine Fuchs
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Article |
Cell–matrix interface regulates dormancy in human colon cancer stem cells
A genetic lineage-tracing system in human colorectal organoids identifies a population of dormant cancer cells that persists during chemotherapy and enables cancer regrowth, and the cell-adhesion molecule COL17A1 has a key role in the process of breaking dormancy.
- Yuki Ohta
- , Masayuki Fujii
- & Toshiro Sato
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Article |
Super-enhancer hypermutation alters oncogene expression in B cell lymphoma
Active super-enhancers are highly and specifically hypermutated in 92% of diffuse large B cell lymphoma samples and display signatures of activation-induced cytidine deaminase activity, leading to the dysregulation of genes encoding B cell developmental regulators and oncogenes.
- Elodie Bal
- , Rahul Kumar
- & Riccardo Dalla-Favera
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Article
| Open AccessStructural basis for SHOC2 modulation of RAS signalling
Cryo-electron microscopy structure, molecular dynamics and biochemical analyses of the SHOC2–PP1C–MRAS complex demonstrate the dependence of the complex formation on RAS–GTP and identify the determinants of RAS isoform preference for SHOC2–PP1C and specificity of the complex for RAF dephosphorylation.
- Nicholas P. D. Liau
- , Matthew C. Johnson
- & Jawahar Sudhamsu
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Article |
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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Article
| Open AccessMitochondrial RNA modifications shape metabolic plasticity in metastasis
- Sylvain Delaunay
- , Gloria Pascual
- & Michaela Frye
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Article |
The metastatic spread of breast cancer accelerates during sleep
A study of patients with breast cancer and mouse models demonstrates that most circulating tumour cells are generated during the rest phase of the circadian rhythm, and that these cells are highly prone to metastasize.
- Zoi Diamantopoulou
- , Francesc Castro-Giner
- & Nicola Aceto
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Article |
cBAF complex components and MYC cooperate early in CD8+ T cell fate
cBAF is a negative determinant of memory T cell fate and the manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.
- Ao Guo
- , Hongling Huang
- & Douglas R. Green
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Article |
Deciphering the immunopeptidome in vivo reveals new tumour antigens
A newly developed genetically engineered mouse model enables the analysis of specific antigen presentation in vivo, providing insights into the tumour immunopeptidome and cancer progression.
- Alex M. Jaeger
- , Lauren E. Stopfer
- & Tyler Jacks
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Article |
A pan-cancer compendium of chromosomal instability
Copy number signatures characterize different types of chromosomal instability and predict drug response.
- Ruben M. Drews
- , Barbara Hernando
- & Florian Markowetz
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Article
| Open AccessSignatures of copy number alterations in human cancer
A new framework enables a pan-cancer reference set of copy number signatures derived from allele-specific profiles from different experimental assays.
- Christopher D. Steele
- , Ammal Abbasi
- & Nischalan Pillay
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Article |
cGAS–STING drives the IL-6-dependent survival of chromosomally instable cancers
The survival of cells with chromosomal instability (CIN) depends on the cGAS–STING pathway, in which IL-6 and its receptor have a key role; this vulnerability can be exploited to treat tumours that display CIN.
- Christy Hong
- , Michael Schubert
- & Floris Foijer
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Article
| Open AccessThe renal lineage factor PAX8 controls oncogenic signalling in kidney cancer
The lineage transcription factor PAX8 is shown to play a pivotal part in determining cancer risk in clear cell renal cell carcinoma, providing insights into how genetic mutations lead to specific types of cancer.
- Saroor A. Patel
- , Shoko Hirosue
- & Sakari Vanharanta
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Article |
Potentiating adoptive cell therapy using synthetic IL-9 receptors
Synthetic chimeric orthogonal IL-2 receptors that incorporate the intracellular domain of receptors for other γ-chain cytokines such as IL-9 can reroute orthogonal signalling and alter the phenotype of T cells to improve anti-tumour responses.
- Anusha Kalbasi
- , Mikko Siurala
- & K. Christopher Garcia
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Article
| Open AccessThe longitudinal dynamics and natural history of clonal haematopoiesis
A long-term study of 385 human donors reports that driver gene mutations and age determine the lifelong dynamics of clonal haematopoiesis
- Margarete A. Fabre
- , José Guilherme de Almeida
- & George S. Vassiliou
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Article |
Stromal changes in the aged lung induce an emergence from melanoma dormancy
Changes in the microenvironment of the aged lung relative to younger lung tissue can lead to the reactivation of dormant melanoma cells through a mechanism that involves a decrease in WNT5A and AXL signalling and an increase in MERTK.
- Mitchell E. Fane
- , Yash Chhabra
- & Ashani T. Weeraratna
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Article |
A vaccine targeting resistant tumours by dual T cell plus NK cell attack
A vaccine targeting stress proteins expressed by many cancers blocks a tumour escape mechanism, enabling protective immunity mediated by diverse T cell and NK cell populations.
- Soumya Badrinath
- , Maxence O. Dellacherie
- & Kai W. Wucherpfennig
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Article |
ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis
A small molecule can bypass the RNA-editing enzyme ADAR1 to directly activate the Z-form nucleic acid sensor ZBP1, induce necroptosis in tumour fibroblasts and reverse resistance to immune checkpoint blockade in mouse models of melanoma.
- Ting Zhang
- , Chaoran Yin
- & Siddharth Balachandran
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Article
| Open AccessNeoantigen quality predicts immunoediting in survivors of pancreatic cancer
The human immune system naturally edits cancers of high-quality neoantigens.
- Marta Łuksza
- , Zachary M. Sethna
- & Vinod P. Balachandran
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Article |
PHGDH heterogeneity potentiates cancer cell dissemination and metastasis
PHDGH heterogeneity in primary tumours could be a sign of tumour aggressiveness.
- Matteo Rossi
- , Patricia Altea-Manzano
- & Sarah-Maria Fendt
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Article |
OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage
The POU2F3–OCA-T complex is the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft-cell-like small-cell lung cancer.
- Xiaoli S. Wu
- , Xue-Yan He
- & Christopher R. Vakoc
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Article |
Olfactory sensory experience regulates gliomagenesis via neuronal IGF1
A mouse model of gliomagenesis reveals that olfaction can directly regulate the genesis of gliomas, showing that sensory experience and gliomagenesis are linked and providing insight into the neural circuitry involved.
- Pengxiang Chen
- , Wei Wang
- & Chong Liu
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Article
| Open AccessFundamental immune–oncogenicity trade-offs define driver mutation fitness
A mathematical framework to estimate the fitness of cancer driver mutations by integrating mutational bias, oncogenicity and immunogenicity finds fundamental trade-offs in cancer evolution.
- David Hoyos
- , Roberta Zappasodi
- & Benjamin D. Greenbaum
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Article
| Open AccessExtricating human tumour immune alterations from tissue inflammation
Complementary single-cell approaches show that a population of regulatory T cells co-expressing ICOS and IL-1 receptor type 1 is highly enriched in tumours but not in site-matched inflamed non-malignant tissue.
- Florian Mair
- , Jami R. Erickson
- & Martin Prlic
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Article |
Landscape of helper and regulatory antitumour CD4+ T cells in melanoma
A survey of the CD4+ T cells in human melanomas indicates that immune evasion is mediated through direct stimulation of neoantigen-specific tumour-reactive regulatory T cells by HLA class II-positive melanoma cells.
- Giacomo Oliveira
- , Kari Stromhaug
- & Catherine J. Wu
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Article
| Open AccessIntermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs
A study using a mouse solid tumour model suggests that adjusting the dosing frequency of the PI3Kδ inhibitor AMG319 in the treatment of human cancers could decrease tumour growth with fewer adverse effects.
- Simon Eschweiler
- , Ciro Ramírez-Suástegui
- & Christian H. Ottensmeier
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Article |
β-Hydroxybutyrate suppresses colorectal cancer
The growth of colorectal cancer is reduced by ketogenic diet consumption, the properties of which are mediated by the ketone body β-hydroxybutyrate.
- Oxana Dmitrieva-Posocco
- , Andrea C. Wong
- & Maayan Levy
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Article
| Open AccessCCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition
Genome-scale CRISPR–Cas9-based synthetic lethality screens identify PKMYT1 as a potential therapeutic target in tumours with CCNE1 amplification.
- David Gallo
- , Jordan T. F. Young
- & Daniel Durocher
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Article
| Open AccessSomatic mutation rates scale with lifespan across mammals
Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.
- Alex Cagan
- , Adrian Baez-Ortega
- & Iñigo Martincorena
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Article |
CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours
A genome-wide CRISPR knockout screen in a model of glioblastoma shows that killing by chimeric antigen receptor T cells requires interferon-γ receptor-dependent adhesion to tumour cells, but cytotoxicity of liquid tumours does not rely on this pathway.
- Rebecca C. Larson
- , Michael C. Kann
- & Marcela V. Maus
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Article |
Anatomic position determines oncogenic specificity in melanoma
In a zebrafish model of human cutaneous and acral melanomas, CRKL amplification causes tumours to favour a fin location, indicating that tumour location is determined by both the driver oncogenes and the pre-existing positional identity gene program.
- Joshua M. Weiss
- , Miranda V. Hunter
- & Richard M. White
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Article
| Open AccessNivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer
Results in the CheckMate 649 phase 3 trial for first-line combined nivolumab and chemotherapy treatment continue to show clinically meaningful efficacy in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma after 24 months, with no new safety signals.
- Kohei Shitara
- , Jaffer A. Ajani
- & Yelena Y. Janjigian
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Article |
Androgen receptor activity in T cells limits checkpoint blockade efficacy
. Androgen-receptor blockade can overcome immunotherapy resistance in prostate cancer by intrinsically enhancing T cell function and IFNγ responses.
- Xiangnan Guan
- , Fanny Polesso
- & Amy E. Moran
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Article |
A genome-scale screen for synthetic drivers of T cell proliferation
A genome-scale gain-of-function screen using overexpression of nearly 12,000 open reading frames (ORFs) identifies positive regulators of human T cell function and suggests that ORF-based screens could be applied clinically to improve T cell therapies.
- Mateusz Legut
- , Zoran Gajic
- & Neville E. Sanjana
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Article |
A non-canonical tricarboxylic acid cycle underlies cellular identity
A non-canonical tricarboxylic acid cycle is required for changes in cell state.
- Paige K. Arnold
- , Benjamin T. Jackson
- & Lydia W. S. Finley
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Article
| Open AccessTryptophan depletion results in tryptophan-to-phenylalanine substitutants
Tryptophan depletion, which occurs in tumours, results in in-frame translation across tryptophan-encoding codons by phenylalanine substitution.
- Abhijeet Pataskar
- , Julien Champagne
- & Reuven Agami
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Article |
Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers
A translationally silent KRASG60G mutation, preventing the formation of a cryptic splice donor site and enabling expression of KRAS(Q61K), reveals a vulnerability in RASQ61 cancers that are therapeutically exploitable in a mutant-selective manner.
- Yoshihisa Kobayashi
- , Chhayheng Chhoeu
- & Pasi A. Jänne
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Article
| Open AccessEffective drug combinations in breast, colon and pancreatic cancer cells
A survey of potency and efficacy of 2,025 clinically relevant two-drug combinations against 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines identifies rare synergistic effects of anticancer drugs, informing rational combination treatments for specific cancer subtypes.
- Patricia Jaaks
- , Elizabeth A. Coker
- & Mathew J. Garnett
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Article |
A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells
A trispecific antibody targeting HER2 and T cells stimulates CD4 T cell-dependent inhibition of of breast cancer cell proliferation in vitro and tumor regression in a humanized mouse model.
- Edward Seung
- , Zhen Xing
- & Gary J. Nabel
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Article
| Open AccessMapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA
An analysis of clustered substitutions and indels across 30 cancer types provides insight into the role of APOBEC3 in giving rise to clustered mutation events through its activity on extrachromosomal DNA.
- Erik N. Bergstrom
- , Jens Luebeck
- & Ludmil B. Alexandrov
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Article |
Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias
Extracellular glioblastoma-associated mutations reduce the ability of the epidermal growth factor receptor to distinguish between its ligands.
- Chun Hu
- , Carlos A. Leche II
- & Mark A. Lemmon
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Article
| Open AccessSignatures of TOP1 transcription-associated mutagenesis in cancer and germline
Defective ribonucleotide excision repair causes ID4, an indel cancer signature characterized by deletions of 2–5 base pairs.
- Martin A. M. Reijns
- , David A. Parry
- & Andrew P. Jackson
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Article
| Open AccessGD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas
A phase I dose-escalation trial of GD2-CAR T cells in children and young adults with diffuse midline gliomas to assess the feasibility of manufacturing, safety and tolerability, and to preliminarily assess efficacy.
- Robbie G. Majzner
- , Sneha Ramakrishna
- & Michelle Monje
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