Featured
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| Open AccessProteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies
The mechanisms of resistance to therapy in gastric cancer remain to be explored. Here, proteomic profiling of 206 tumour tissues from patients treated with chemotherapy and anti-HER2-based therapy results in the identification of four molecular subtypes and the development of prognostic models.
- Yan Li
- , Chen Xu
- & Chen Ding
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Article
| Open AccessA protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses
Manganese has a crucial role in cGAS-STING-mediated DNA sensing and has emerged as a STING agonist. Here the authors report the design and characterization of a nanosystem incorporating manganese ions and the chemotherapeutic drug β-lapachone, inducing T-cell mediated anti-tumor immune responses in preclinical cancer models.
- Xuan Wang
- , Yingqi Liu
- & Zhong Luo
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Article
| Open AccessUSP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer
IDO1-mediated tryptophan metabolism plays an important role in creating an immunosuppressive tumour microenvironment. Here, the authors show that deubiquitinase USP14 regulates immune suppression by inducing IDO1 stabilization and suggest USP14 as a potential therapeutic target to improve immunotherapy in colorectal cancer.
- Dongni Shi
- , Xianqiu Wu
- & Wenting Liao
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Article
| Open AccessThe comparison of cancer gene mutation frequencies in Chinese and U.S. patient populations
Frequency of cancer-related gene mutations can vary between populations. Here, the authors show differences in TP53 and other gene mutations between the U.S. and Chinese patients, and analyse differences in environmental risk factors to demonstrate that population-specific factors should be considered when discussing cancer risk.
- Fayang Ma
- , Kyle Laster
- & Zigang Dong
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Article
| Open AccessGraphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells
DNA methyltransferase 3A, a mutated gene associated with hematologic malignancies in age-related clonal haematopoiesis lacks targeted therapies. Here, the authors screen carbon nanomaterials and find graphdiyne oxide binds to mutant cells and disrupts cellular processes with a therapeutic effect in vitro and in vivo.
- Qiwei Wang
- , Ying Liu
- & Pengxu Qian
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Article
| Open AccessModeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers
Identifying structural variants (SVs) under positive selection in cancer is challenging. Here, the authors develop CSVDriver, a method that computes SV breakpoint proximity and the contribution of elements such as topologically associating domains, and identifies loci that show signs of positive selection and contain known and putative drivers.
- Alexander Martinez-Fundichely
- , Austin Dixon
- & Ekta Khurana
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Article
| Open AccessRAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma
Mutations in RAS oncogenes and related pathways are frequent in lung cancers. Here, the authors derive a RAS gene expression signature and a machine learning classifier to predict drug response and clinical outcomes in lung adenocarcinoma and other solid tumours, with improved performance over KRAS mutations alone.
- Philip East
- , Gavin P. Kelly
- & Sophie de Carné Trécesson
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Article
| Open AccessGenomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors
Fusion genes have been proposed as a potential mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Here, the authors identify gene fusions that are associated with resistance to EGFR TKIs in non-small cell lung cancers, and test how these fusions impact the response to EGFR TKIs in vitro.
- Yoshihisa Kobayashi
- , Geoffrey R. Oxnard
- & Pasi A. Jänne
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Article
| Open AccessCharacterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy
Retinoblastoma response to treatment is difficult to predict. Here, the authors show that DNA methylation of cfDNA from aqueous humour is altered in retinoblastoma patients and can be used to identify the molecular subtypes and potentially predict treatment response.
- Hong-Tao Li
- , Liya Xu
- & Jesse L. Berry
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Article
| Open AccessAn EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms
Chemoresistance is a main limitation for the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, the authors show that an antibody drug conjugate-like compound targeting both EGFR and HER2 overcomes gemcitabine resistance in PDAC preclinical models by mechanisms involving the tumour suppressor SMAD4.
- Hongjuan Yao
- , Wenping Song
- & Liang Li
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Article
| Open AccessSingle cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast
Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-γ.
- Vincent Geldhof
- , Laura P. M. H. de Rooij
- & Peter Carmeliet
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Article
| Open AccessDNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival
Glucocorticoids, such as dexamethasone, are used as anti-inflammatory and immunosuppressive drugs, however patients may exhibit resistance or side effects. Here the authors propose that a dexamethasone related neutrophil-specific DNA methylation index can be used as a marker of glucocorticoid exposure and response and as a prognostic factor in brain tumor survival.
- J. K. Wiencke
- , Annette M. Molinaro
- & Karl T. Kelsey
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Article
| Open AccessAngiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells
Glioma stem-like cells (GSCs) exhibit plasticity during proneural-to-mesenchymal transition. Here the authors show that extracellular vesicles from endothelial cells can promote this transition of GSCs through activation of MMPs and NFkB, and inactivation of NOTCH.
- Lata Adnani
- , Jordan Kassouf
- & Janusz Rak
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Article
| Open AccessARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer
ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated colorectal cancer tumors, however, its relationship with treatment response remains to be explored. Here, the authors suggest that ARID1A mutations may confer intrinsic and acquired resistance to cetuximab treatment.
- Radia M. Johnson
- , Xueping Qu
- & Carlos Bais
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Article
| Open AccessIntegrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia
Relapsed pediatric acute myeloid leukemia is associated with poor prognosis. Here, the authors use RNA-seq data from 1503 primary samples to create a combined transcriptional and cytomolecular signature to improve relapse risk prediction.
- Benjamin J. Huang
- , Jenny L. Smith
- & Soheil Meshinchi
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Article
| Open AccessConserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer
TERT promoter mutations are the most common noncoding alterations in cancers, although some remain to be characterised. Here, the authors identify TERT promoter duplications across seven cancer types that are functionally equivalent to well-known hotspot TERT mutations and are clonal in a multifocal glioblastoma patient.
- Carter J. Barger
- , Abigail K. Suwala
- & Joseph F. Costello
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Article
| Open AccessInhibition of UBA6 by inosine augments tumour immunogenicity and responses
The metabolic environment of tumours has wide-ranging effects on the anti-tumour immune response and the outcome of immune therapy. Authors show here that the purine metabolite inosine enhances tumour immunogenicity and thus immune checkpoint blockade therapy response by inhibiting the ubiquitin-activating enzyme UBA6 in tumour cells.
- Lei Zhang
- , Li Jiang
- & Baokun He
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Article
| Open AccessPangenomic analysis of Chinese gastric cancer
Human pan-genomics are increasing our knowledge of genomic diversity and genetic factors in disease. Here, the authors built a gastric cancer pan-genome that included the sequences of Chinese Han patients, and predicted putative and previously unaligned genes associated with gastric cancer.
- Yingyan Yu
- , Zhen Zhang
- & Zhenggang Zhu
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Article
| Open AccessReconstitution of microtubule into GTP-responsive nanocapsules
GTP-triggered release from drug carriers has huge potential in cancer therapy but current carriers suffers from off target release due to ATP also acting as a trigger. Here, the authors report on the development of a microtubule capsule which is engineered to be responsive to only GTP not ATP and demonstrate targeted drug delivery.
- Noriyuki Uchida
- , Ai Kohata
- & Takuzo Aida
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Article
| Open AccessEpigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia
Different molecular subtypes defined by specific gene rearrangements have been described for acute lymphoblastic leukaemia (ALL). Here, the authors show that ZNF384 fusion activates FLT3 expression conferring a therapeutic vulnerability for ZNF384- rearranged ALL subtype.
- Xujie Zhao
- , Ping Wang
- & Jun J. Yang
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Article
| Open AccessA pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma
In patients with locally advanced resectable oral squamous cell carcinoma (OSCC), the risk of recurrence and metastasis following treatment is high. Here, a phase I clinical trial reports safety and pathological response of neoadjuvant camrelizumab and apatinib in patients with locally advanced resectable OSCC.
- Wu-tong Ju
- , Rong-hui Xia
- & Lai-ping Zhong
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Article
| Open AccessFatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37
Tetraspanin CD37 deficiency has been reported as a prognostic marker for aggressive B-cell lymphoma. Here, the authors show that CD37 interacts with the fatty acid transporter 1 to inhibit palmitate uptake and its deficiency leads to increased fatty acid metabolism which promotes tumorigenesis in B-cell lymphoma.
- Rens Peeters
- , Jorge Cuenca-Escalona
- & Annemiek B. van Spriel
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Article
| Open AccessInterleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm
Chronic inflammation is frequently observed in patients with myeloproliferative neoplasms (MPN). Here the authors observe elevated levels of IL-1α and IL-1β in MPN patients and show that IL-1 contributes to clonal expansion and bone marrow fibrosis in a mouse model of MPN, proposing targeting of IL1R1 as therapeutic intervention.
- Mohammed Ferdous-Ur Rahman
- , Yue Yang
- & Golam Mohi
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Article
| Open AccessInhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm
Inflammatory cytokines are elevated in patients with myeloproliferative neoplasms (MPN). Here the authors show that the JAK2-V617F mutation is associated with increased expression of IL-1 in MPN patients and that loss of IL-1β in JAK2-V617F mutant hematopoietic cells reduces MPN symptoms and myelofibrosis in a mouse model.
- Shivam Rai
- , Elodie Grockowiak
- & Radek C. Skoda
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Article
| Open AccessCtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway
RNA has been implicated in DNA repair. This work shows that the interplay of RNAPII-generated nascent RNA, RNA:DNA hybrids and the resection factor CtIP guide DNA double strand break repair pathway choice towards error-free homologous recombination.
- Daniel Gómez-Cabello
- , George Pappas
- & Jiri Bartek
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Article
| Open AccessIn vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response
Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
- Aditi Sahu
- , Kivanc Kose
- & Milind Rajadhyaksha
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Article
| Open AccessBiomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Biomarkers predictive of response to T cell therapy remain to be better defined. This study identifies potential predictive and pharmacodynamic markers of response to NY-ESO-1 T-cell therapy in a solid tumor that may inform lymphodepletion, cell dose, and strategies to enhance anticancer efficacy.
- Alexandra Gyurdieva
- , Stefan Zajic
- & Ioanna Eleftheriadou
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Article
| Open AccessIntegrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics
The mutational landscape of esophageal squamous cell cancer (ESCC) remains poorly characterised. Here, the authors integrate multiple published datasets and systematically evaluate the mutational signatures and the related genomic and clinical features in ESCC.
- Minghao Li
- , Zicheng Zhang
- & Baosheng Li
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Article
| Open AccessHigh p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.
- Marta Palafox
- , Laia Monserrat
- & Violeta Serra
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| Open AccessPotential solutions for manufacture of CAR T cells in cancer immunotherapy
CAR T cell therapy is an effective cancer treatment, but biological and manufacturing hurdles hamper its broad breakthrough. Although the first step towards automated manufacture of CAR cells has been taken, new technologies are needed to enable the treatment of large patient groups.
- Ulrich Blache
- , Georg Popp
- & Stephan Fricke
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Article
| Open AccessOXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling
Worst pattern of invasion (WPOI) is a parameter used to quantify tumor invasiveness of oral squamous cell carcinoma (OSCC). Here the authors show that a fibroblast subset characterized by the expression of the oxytocin receptor is enriched in highly invasive WPOI 4-5 OSCC tumors and can be targeted to reduce the desmoplastic stroma and tumor metastasis.
- Liang Ding
- , Yong Fu
- & Yanhong Ni
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Article
| Open AccessMulti-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.’
- Tomoya Isobe
- , Masatoshi Takagi
- & Junko Takita
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Article
| Open AccessEpithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence
The study of tumour dormancy is limited by suitable in vivo models. Here the authors show that mammary intraductal breast cancer (BC) xenografts model estrogen receptor α-positive (ER+) BC dormancy and rapid metastatic progression characteristic of triple-negative (TN) BC. The dormant disseminated ER+ BC cells display characteristics of epithelial-mesenchymal plasticity and forced expression of E-cadherin allows them to overcome dormancy.
- Patrick Aouad
- , Yueyun Zhang
- & Cathrin Brisken
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Article
| Open AccessSelective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling
Tumor loss of IFN-γ signalling is a major mechanism of resistance to immune checkpoint blockers. Here the authors report that melanoma cells with knockout of IFNγR1 show constitutive JAK1/2 activation and that the JAK1/2 inhibitor ruxolitinib can overcome resistance to anti-CTLA-4 therapy.
- Hongxing Shen
- , Fengyuan Huang
- & Lewis Zhichang Shi
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Article
| Open AccessMultifunctional nanoparticle potentiates the in situ vaccination effect of radiation therapy and enhances response to immune checkpoint blockade
Radiotherapy can activate an in situ vaccine response and promote response to immune checkpoint inhibitors. Here the authors design a multifunctional nanoparticle to enhance tumor antigen presentation and modulate the tumor immune microenvironment following radiotherapy, showing improved anti-tumor immune responses in radiotherapy-treated tumors when combined with immune checkpoint inhibitors.
- Ying Zhang
- , Raghava N. Sriramaneni
- & Zachary S. Morris
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Article
| Open AccessA nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer
Cisplatin is the most frequently used chemotherapeutic agent for the treatment of patients with oral cavity squamous cell carcinoma (OCSCC), however, systemic administration is often associated with dose limiting side effects. Here the authors design and test a nano-engineered patch system (PRV111) for the local delivery of cisplatin-loaded chitosan nanoparticles and report the results of a phase 1/2 clinical trial of PRV111 in patients with OCSCC.
- Manijeh Goldberg
- , Aaron Manzi
- & Evgeny Izumchenko
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Article
| Open AccessA lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy
Combination therapies simultaneously inhibiting different therapeutic targets in cancer is challenged by individual pharmacokinetic profiles. Here, the authors generate an orally provided multi-targeted kinase inhibitor that is lymphatic absorbed and increases survival in a murine model of myelofibrosis.
- Brian D. Ross
- , Youngsoon Jang
- & Marcian E. Van Dort
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Article
| Open AccessSingle cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma
The components of the glioma immune microenvironment and their roles in promoting tumourigenesis remain poorly understood. Here, the use of single-cell RNA sequencing and multiplexed tissue-imaging in adult and pediatric high-grade gliomas reveals the activity and spatial organization of the immunomodulatory purinergic signaling pathway.
- Shannon Coy
- , Shu Wang
- & Sandro Santagata
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Article
| Open AccessGeneration of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance
Modelling of aggressive lymphomas, such as double hit lymphoma, has been challenging. Here the authors engineer a CRISPR activation mouse to enable the generation of these aggressive lymphomas and identify the pro-survival BCL-2 protein A1 as a venetoclax resistance factor.
- Yexuan Deng
- , Sarah T. Diepstraten
- & Marco J. Herold
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Article
| Open AccessUltra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells
As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here the authors use next generation sequencing to achieve high sequencing depth and demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants.
- M. Kyle Cromer
- , Valentin V. Barsan
- & Matthew H. Porteus
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Article
| Open AccessBlocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer
Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.
- Andre Lima Queiroz
- , Ezequiel Dantas
- & Marcus D. Goncalves
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Article
| Open AccessUnified classification and risk-stratification in Acute Myeloid Leukemia
Classification and risk-stratification for Acute Myeloid Leukemia (AML) at diagnosis are primarily based on cytogenetics and only a few gene mutations. Here, the authors study the genomic landscape of 3653 AML patients and characterize 16 non-overlapping molecular subgroups of clinical relevance for disease classification and risk prognostication.
- Yanis Tazi
- , Juan E. Arango-Ossa
- & Elli Papaemmanuil
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Article
| Open AccessReactive oxygen species-responsive and Raman-traceable hydrogel combining photodynamic and immune therapy for postsurgical cancer treatment
Combined immune checkpoint blockade (ICB) and photodynamic therapies have huge potential but suffer from possible damage of the antibodies. Here, the authors create a ROS-responsive hydrogel that protects the ICB antibodies and allows for sustained co-delivery and demonstrate restrained regrowth of tumours in vivo.
- Yiyi Zhang
- , Sidan Tian
- & Liang Luo
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Article
| Open AccessSerine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers
Metabolic reprogramming is associated with cancer development and therapy resistance. Here, the authors show that downregulation of the serine biosynthesis enzyme PHGDH in a fraction of patients is associated with relapse in platinum-treated ovarian cancers and to NAD+ and PARP activity upregulation.
- Tom Van Nyen
- , Mélanie Planque
- & Frédéric Amant
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Article
| Open AccessMolecular characterization of colorectal cancer related peritoneal metastatic disease
Colorectal cancer can lead to the development of peritoneal metastases, which are associated with worse disease outcome. Here, the authors characterize peritoneal metastases from 52 patients using RNA-seq and mutational sequencing and show a distinct molecular subtype.
- Kristiaan J. Lenos
- , Sander Bach
- & Louis Vermeulen
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Article
| Open AccessThe spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states
Spatially and temporally resolved data can improve our understanding of evolution and treatment resistance in multiple myeloma (MM). Here, the authors analyse spatial and longitudinal heterogeneity in MM patients using multi-region sequencing, and identify subclones associated with relapse and therapy resistance.
- Leo Rasche
- , Carolina Schinke
- & Niels Weinhold
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Article
| Open AccessComprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity
The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.
- Lino Möhrmann
- , Maximilian Werner
- & Hanno Glimm
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Article
| Open AccessSpatiotemporal control of engineered bacteria to express interferon-γ by focused ultrasound for tumor immunotherapy
Several approaches have been recently proposed to engineer bacteria for cancer immunotherapy. Here the authors design an ultrasound-responsive bacterium for the controlled release of IFNy at the tumor site, promoting anti-tumor immune responses in preclinical models.
- Yuhao Chen
- , Meng Du
- & Fei Yan
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Article
| Open AccessDNA methylation-based epigenetic signatures predict somatic genomic alterations in gliomas
No clinical assay currently exists to classify glioma tumours based on gene expression. Here, the authors develop a DNA methylation-based classifier, Unified Diagnostic Pipeline (UniD) that identifies genomic alterations and gene expression subtypes of gliomas.
- Jie Yang
- , Qianghu Wang
- & Erik P. Sulman