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| Open AccessSpatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo
Topobiologically complex mini-colons—which enable the faithful in vitro recapitulation of colorectal cancer tumorigenesis and its environmental determinants—offer the possibility to reduce animal use in a wide range of experimental applications.
- L. Francisco Lorenzo-Martín
- , Tania Hübscher
- & Matthias P. Lutolf
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Article
| Open AccessTumour-selective activity of RAS-GTP inhibition in pancreatic cancer
RMC-7977, a multi-selective RAS(ON) inhibitor, exhibits potent tumour-selective activity in multiple pre-clinical models of pancreatic ductal adenocarcinoma through a combination of pharmacology and oncogene dependence.
- Urszula N. Wasko
- , Jingjing Jiang
- & Kenneth P. Olive
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Article
| Open AccessA distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche
A study reveals that Fusobacterium nucleatum subspecies animalis is bifurcated into two distinct clades, and shows that only one of these dominates the colorectal cancer niche, probably through increased colonization of the human gastrointestinal tract.
- Martha Zepeda-Rivera
- , Samuel S. Minot
- & Christopher D. Johnston
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Article |
SOX17 enables immune evasion of early colorectal adenomas and cancers
Transcriptomic and chromatin accessibility analyses of naive and transplanted colon cancer organoids in a mouse model reveal a key role for the transcription factor SOX17 in establishing a permissive immune environment for tumour cells.
- Norihiro Goto
- , Peter M. K. Westcott
- & Ömer H. Yilmaz
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Article |
Deep whole-genome analysis of 494 hepatocellular carcinomas
The Chinese Liver Cancer Atlas project depicts a panoramic genomic landscape of hepatocellular carcinoma, covering candidate coding and non-coding drivers, mutational signatures, extrachromosomal circular DNA, subclonal catastrophic events and detailed evolutionary history.
- Lei Chen
- , Chong Zhang
- & Hongyang Wang
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Article
| Open AccessMatrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver
Structural changes mediated by advanced glycation end-products enhance extracellular matrix viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.
- Weiguo Fan
- , Kolade Adebowale
- & Natalie J. Török
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Article |
IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer
Single-cell and spatial gene expression analyses of pancreatic ductal adenocarcinoma uncover a population of interleukin-1β-expressing macrophages that drive inflammatory reprogramming of neighboring tumour cells leading to disease progression and poor prognosis for patients.
- Nicoletta Caronni
- , Federica La Terza
- & Renato Ostuni
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Matters Arising |
Revisiting the intrinsic mycobiome in pancreatic cancer
- Ashley A. Fletcher
- , Matthew S. Kelly
- & Peter J. Allen
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Article |
Histone demethylase KDM5D upregulation drives sex differences in colon cancer
A murine colorectal cancer (CRC) model shows that mutant KRAS-STAT4-mediated upregulation of Y chromosome KDM5D contributes to the sex differences in KRAS-mutant CRC, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS-mutant CRC.
- Jiexi Li
- , Zhengdao Lan
- & Ronald A. DePinho
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Article |
Tumour extracellular vesicles and particles induce liver metabolic dysfunction
Remote tumours cause liver dysfunction by releasing extracellular vesicles and particles containing palmitic acid, which induces TNF signalling in Kupffer cells, resulting in inflammation, fatty deposits and metabolic dysregulation, thus both reducing the efficacy and increasing the toxicity of chemotherapies.
- Gang Wang
- , Jianlong Li
- & David Lyden
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Article
| Open AccessUridine-derived ribose fuels glucose-restricted pancreatic cancer
A metabolite screen of pancreatic cells shows that pancreatic cancer cells metabolize uridine-derived ribose via UPP1, supporting redox balance, survival and proliferation.
- Zeribe C. Nwosu
- , Matthew H. Ward
- & Costas A. Lyssiotis
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Article
| Open AccessPersonalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer
A phase I clinical trial of an adjuvant personalized mRNA neoantigen vaccine, autogene cevumeran, in patients with pancreatic ductal carcinoma demonstrates that the vaccine can induce T cell activity that may correlate with delayed recurrence of disease.
- Luis A. Rojas
- , Zachary Sethna
- & Vinod P. Balachandran
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Article
| Open AccessExtrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus
An analysis of whole-genome sequencing data from patients with Barrett’s oesophagus or oesophageal ademocarcinoma shows that extrachromosomal DNA (ecDNA) is strongly associated with cancer progression, and that a wide range of oncogenes are amplified on ecDNAs.
- Jens Luebeck
- , Alvin Wei Tian Ng
- & Paul S. Mischel
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Article |
Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer
Pancreatic ductal adenocarcinoma cells show a specific dependency on ornithine aminotransferase-mediated ornithine synthesis from glutamine, providing an opportunity to develop targeted therapies with minimal toxicity for this cancer.
- Min-Sik Lee
- , Courtney Dennis
- & Nada Y. Kalaany
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Article
| Open Accessγδ T cells are effectors of immunotherapy in cancers with HLA class I defects
γδ T cells contribute to the response to immune checkpoint blockade treatment in patients with HLA-class-I-negative DNA mismatch repair-deficient colon cancers. .
- Natasja L. de Vries
- , Joris van de Haar
- & Emile E. Voest
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Article
| 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 |
Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation
Chemotherapy-induced death of colon cancer cells causes ATP release triggering P2X4 to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders them sensitive to mTOR inhibition.
- Mark Schmitt
- , Fatih Ceteci
- & Florian R. Greten
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Article |
Liver tumour immune microenvironment subtypes and neutrophil heterogeneity
Tumour-associated neutrophil populations enriched in the myeloid-cell-enriched tumour immune microenvironment subtype are associated with unfavourable prognosis in humans and mice with liver cancer.
- Ruidong Xue
- , Qiming Zhang
- & Ning Zhang
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Article
| 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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Article
| 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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Article |
Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis
Subpopulations of cytokine-producing and myofibroblastic hepatic stellate cells, identified by single-cell RNA sequencing, protect against or promote the development of hepatocellular carcinoma via high expression of hepatocyte growth factor or type I collagen, respectively..
- Aveline Filliol
- , Yoshinobu Saito
- & Robert F. Schwabe
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Article
| Open AccessAntibody targeting of E3 ubiquitin ligases for receptor degradation
Membrane-bound E3 ubiquitin ligases RNF43 and ZNRF3 are overexpressed in colorectal cancer, and can be repurposed using proteolysis-targeting antibodies (PROTABs) to selectively degrade cell-surface receptors in tumours.
- Hadir Marei
- , Wen-Ting K. Tsai
- & Felipe de Sousa e Melo
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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 |
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 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
| 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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The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer
Interim analysis of a phase III clinical trial of HER2-positive gastric adenocarinoma shows pembrolizumab plus trastuzumab and chemotherapy improves response rates compared with trastuzumab and chemotherapy alone.
- Yelena Y. Janjigian
- , Akihito Kawazoe
- & Hyun Cheol Chung
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Article |
Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis
A rare population of acinar cells expressing telomerase reverse transcriptase renew the acinar cell compartment during homeostasis, and are potential sources of premalignant cells in pancreatic carcinogenesis.
- Patrick Neuhöfer
- , Caitlin M. Roake
- & Steven E. Artandi
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Article |
Tracing oncogene-driven remodelling of the intestinal stem cell niche
By inducing changes in surrounding tissue, mutant intestinal stem cells create an unfavourable niche environment that gives them a competitive advantage over non-mutant neighbours.
- Min Kyu Yum
- , Seungmin Han
- & Benjamin D. Simons
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Article |
Apc-mutant cells act as supercompetitors in intestinal tumour initiation
Using experiments in organoids and in vivo in mice, the authors show that Apc-mutant cells act as supercompetitors to initiate the formation of adenomas.
- Sanne M. van Neerven
- , Nina E. de Groot
- & Louis Vermeulen
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Article |
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
NOTUM from Apc-mutant cells acts as a key mediator during the early stages of mutation fixation and drives the formation of intestinal adenomas.
- Dustin J. Flanagan
- , Nalle Pentinmikko
- & Owen J. Sansom
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Article |
A gene–environment-induced epigenetic program initiates tumorigenesis
In mouse models of pancreatic cancer, a cooperative interaction between tissue damage and Kras gene mutation rapidly induces cancer-associated chromatin states in pre-malignant tissue, leading to gene dysregulation and neoplastic transformation.
- Direna Alonso-Curbelo
- , Yu-Jui Ho
- & Scott W. Lowe
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Article |
Repeat expansions confer WRN dependence in microsatellite-unstable cancers
In cells with microsatellite instability, expanded TA-dinucleotide repeats form cruciform structures that stall replication forks and cause chromosome shattering in the absence of the WRN helicase.
- Niek van Wietmarschen
- , Sriram Sridharan
- & André Nussenzweig
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Review Article |
Host–microbiota maladaptation in colorectal cancer
This Review describes the interplay between host genetics, host immunity and the gut microbiome in the modulation of colorectal cancer, and discusses the role of specific bacterial species and metabolites alongside technological advances that will facilitate more in-depth investigation of the microbiome in disease.
- Alina Janney
- , Fiona Powrie
- & Elizabeth H. Mann
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Article |
The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic
In two mouse models of intestinal cancer, mutant p53 has an oncogenic effect in the distal gut but a tumour-suppressive effect in the proximal gut, and these opposing properties are determined by the gut microbiome.
- Eliran Kadosh
- , Irit Snir-Alkalay
- & Yinon Ben-Neriah
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Article |
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Inhibition of the autophagy–lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8+ T cells.
- Keisuke Yamamoto
- , Anthony Venida
- & Alec C. Kimmelman
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Article |
Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche
Single-cell RNA-sequencing analysis of intestinal mesenchyme identified a population of fibroblasts that produce prostaglandin E2, which, when disrupted, prevented initiation of intestinal tumours.
- Manolis Roulis
- , Aimilios Kaklamanos
- & Richard A. Flavell
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Article |
ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity
Tumour-infiltrating group 2 innate lymphoid cells prime CD8+ T cells and amplify the anti-tumour effects of PD-1 blockade in pancreatic ductal adenocarcinoma.
- John Alec Moral
- , Joanne Leung
- & Vinod P. Balachandran
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Article |
AQP5 enriches for stem cells and cancer origins in the distal stomach
AQP5 is identified as a marker for pyloric stem cells in humans and mice, and stem cells in the AQP5+ compartment are shown to be a source of invasive gastric cancer in mouse models.
- Si Hui Tan
- , Yada Swathi
- & Nick Barker
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Article |
Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis
In patients with ulcerative colitis, chronic inflammation can lead to remodelling of the colorectal epithelium through positive selection of clones with mutations in genes related to IL-17 signalling, which, however, might be negatively selected during colitis-associated carcinogenesis.
- Nobuyuki Kakiuchi
- , Kenichi Yoshida
- & Seishi Ogawa
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Article |
The landscape of somatic mutation in normal colorectal epithelial cells
Genome sequencing of hundreds of normal colonic crypts from 42 individuals sheds light on mutational processes and driver mutations in normal colorectal epithelial cells.
- Henry Lee-Six
- , Sigurgeir Olafsson
- & Michael R. Stratton
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Article |
Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs
Gastrointestinal stromal tumours can be initiated by gain-of-function mutations of the KIT or PDGFRA oncogenes but also by loss of the metabolic complex succinate dehydrogenase (SDH), which leads to DNA hypermethylation; this study shows that in SDH-deficient tumours, displacement of CTCF insulators by DNA methylation activates oncogene expression, illustrating how epigenetic alterations can drive oncogenic signalling in the absence of kinase mutations.
- William A. Flavahan
- , Yotam Drier
- & Bradley E. Bernstein
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Article |
The U1 spliceosomal RNA is recurrently mutated in multiple cancers
A highly recurrent A>C somatic mutation in U1 small nuclear RNA, which alters the splicing pattern of genes that include known drivers of cancer, is identified in several types of tumour.
- Shimin Shuai
- , Hiromichi Suzuki
- & Lincoln D. Stein
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Letter |
Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring
A systematic proteomic investigation of disease mediators secreted by pancreatic stellate cells identifies leukaemia inhibitory factor (LIF) as a key factor that acts on cancer cells, promoting tumour progression and chemoresistance.
- Yu Shi
- , Weina Gao
- & Tony Hunter
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Letter |
Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer
In an inducible mouse model of pancreatic ductal adenocarcinoma, the signalling defect that underlies 90% of these tumours causes increased cell-surface expression of syndecan 1, leading to misregulation of macropinocytosis, and linking the defective signalling with nutrient-salvage pathways.
- Wantong Yao
- , Johnathon L. Rose
- & Giulio F. Draetta
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Letter |
Hepatocytes direct the formation of a pro-metastatic niche in the liver
Pancreatic cancer activates IL-6–STAT3 signalling in hepatocytes to induce the formation of a pro-metastatic niche in the liver.
- Jae W. Lee
- , Meredith L. Stone
- & Gregory L. Beatty
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Letter |
Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma
A subtype of early-stage hepatocellular carcinoma characterized by disrupted cholesterol homeostasis and associated with a poor prognosis responds to treatment with the SOAT1 inhibitor avasimibe in a patient-derived xenograft mouse model.
- Ying Jiang
- , Aihua Sun
- & Zesong Li
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Letter |
Interleukin-22 protects intestinal stem cells against genotoxic stress
Sporadic inactivation of the interleukin-22 receptor in the intestinal epithelium of the mouse shows that IL-22 is required for effective activation of the DNA damage response following DNA damage.
- Konrad Gronke
- , Pedro P. Hernández
- & Andreas Diefenbach
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Letter |
Altered exocrine function can drive adipose wasting in early pancreatic cancer
Pancreatic ductal adenocarcinoma in mice induces loss of adipose tissue through altered function of the exocrine pancreas, and supplementing pancreatic enzymes attenuates the wasting of peripheral tissues induced by pancreatic cancer.
- Laura V. Danai
- , Ana Babic
- & Matthew G. Vander Heiden