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| 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 |
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 |
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 |
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 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 |
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 |
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 |
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 |
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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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 |
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
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Article |
Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes
Oncogenic dosage variation along distinct evolutionary routes defines fundamental aspects of pancreatic cancer biology and phenotypic diversification.
- Sebastian Mueller
- , Thomas Engleitner
- & Roland Rad
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Letter |
Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer
The analysis of T-cell antigens in long-term survivors of pancreatic ductal adenocarcinoma suggests that neoantigen immunogenicity and quality, not purely quantity, correlate with survival.
- Vinod P. Balachandran
- , Marta Łuksza
- & Steven D. Leach
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Letter |
Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer
Depletion of malic enzyme 3 in pancreatic cancer cells that have a deletion of the gene for malic enzyme 2 selectively kills the cells, suggesting that the enzyme might represent a therapeutic target for this subset of cancers.
- Prasenjit Dey
- , Joelle Baddour
- & Ronald A. DePinho
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Letter |
A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns
Pancreatic cancer is not caused by a specific series of genetic alterations that occur sequentially but by one, or few, catastrophic events that result in simultaneous oncogenic genetic rearrangements, giving rise to highly aggressive tumours.
- Faiyaz Notta
- , Michelle Chan-Seng-Yue
- & Steven Gallinger
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Letter |
The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression
A study of pancreatic ductal adenocarcinoma shows that cancer cell proliferation is associated with increased expression of proteins that control programmed necrotic cell death and suppress the adaptive immune system.
- Lena Seifert
- , Gregor Werba
- & George Miller
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Article |
Genomic analyses identify molecular subtypes of pancreatic cancer
An integrated genomic analysis of 456 human pancreatic ductal adenocarcinomas identifies four subtypes defined by transcriptional expression profiles and show that these are associated with distinct histopathological characteristics and differential prognosis.
- Peter Bailey
- , David K. Chang
- & Sean M. Grimmond
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Letter |
Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism
The MiT/TFE family of transcription factors is found to coordinate constitutive activation of autophagy and lysosome biogenesis to drive the metabolic programming and malignant growth of pancreatic cancer.
- Rushika M. Perera
- , Svetlana Stoykova
- & Nabeel Bardeesy
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Article |
Glypican-1 identifies cancer exosomes and detects early pancreatic cancer
Glypican-1 identifies cancer exosomes and serves as a biomarker for detection of early pancreatic cancer in patients and mouse models of the disease; the findings may enable early and non-invasive identification, and prevention of malignant cancer.
- Sonia A. Melo
- , Linda B. Luecke
- & Raghu Kalluri
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Article |
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
Exome sequencing and copy number analysis are used to define genomic aberrations in early sporadic pancreatic ductal adenocarcinoma; among the findings are mutations in genes involved in chromatin modification and DNA damage repair, and frequent and diverse somatic aberrations in genes known as embryonic regulators of axon guidance.
- Andrew V. Biankin
- , Nicola Waddell
- & Sean M. Grimmond
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Letter |
RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis
A new method allows the collection of circulating tumour cells (CTCs) despite their rarity; transcriptome sequencing of CTCs could allow identification of pathways involved in metastasis.
- Min Yu
- , David T. Ting
- & Daniel A. Haber
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Research Highlights |
A tumour's Kras behaviour
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Letter |
The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma
An in vivo transposon screen in a pancreatic cancer model identifies frequent inactivation of Usp9x; deletion of Usp9x cooperates with KrasG12D to accelerate rapidly pancreatic tumorigenesis in mice, validating their genetic interaction.
- Pedro A. Pérez-Mancera
- , Alistair G. Rust
- & David A. Tuveson
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Research Highlights |
Tumours yield to pressure relief
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News |
Mouse 'avatars' could aid pancreatic cancer therapy
Personalized mouse model may lead to tailored treatments for patients.
- Carina Dennis
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Research Highlights |
Probing for pancreatic cancer
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Research Highlights |
Laying siege to cancer
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Research Highlights |
Hide no more, tumour
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News |
New lead on deadly pancreatic cancer
Mouse model reveals mechanism of potential therapy for lethal tumours.
- Alison Abbott
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News & Views |
Cancer lessons from mice to humans
New clinical trials report the efficacy of two mechanism-based therapies for treating human pancreatic neuroendocrine tumours. Studies in mouse models have contributed to these success stories, and continue to do so.
- David Tuveson
- & Douglas Hanahan
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News & Views |
Genomic evolution of metastasis
Prognosis for patients with pancreatic cancer is bleak, often owing to late diagnosis. The estimate that at least 15 years pass from tumour initiation to malignancy offers hope for early detection and prevention. See Letters p.1109 & p.1114
- E. Georg Luebeck
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Letter |
The patterns and dynamics of genomic instability in metastatic pancreatic cancer
Pancreatic cancer is highly aggressive, usually because of widespread metastasis. Here, next-generation DNA sequencing has been used to detect genomic rearrangements in 13 patients with pancreatic cancer and to explore clonal relationships among metastases. The results reveal not only considerable inter-patient heterogeneity, but also ongoing genomic instability and evolution during the development of metastases.
- Peter J. Campbell
- , Shinichi Yachida
- & P. Andrew Futreal
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Letter |
Distant metastasis occurs late during the genetic evolution of pancreatic cancer
Here, whole-genome sequencing has been used to analyse primary pancreatic tumours and one or more metastases from the same patients. The findings show that tumours are composed of several geographically distinct subclones, and allow maps to be produced showing how metastatic cancer clones evolve within the primary tumour. Moreover, a quantitative analysis of the timing of the genetic evolution of pancreatic cancer has been performed.
- Shinichi Yachida
- , Siân Jones
- & Christine A. Iacobuzio-Donahue