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| Open AccessThe Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction
Surgery is an important part of treatment for gastric adenocarcinoma, however, the consensus on perioperative care is less clear. Here, the authors report the results of a phase II clinical trial investigating neoadjuvant camrelizumab with concurrent chemoradiotherapy, followed by surgery for the treatment of advanced gastric adenocarcinoma.
- Zhaoqing Tang
- , Yan Wang
- & Yihong Sun
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Article
| Open AccessAn mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.
- Kaushal Asrani
- , Juhyung Woo
- & Tamara L. Lotan
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| Open AccessSystematic characterization of cancer transcriptome at transcript resolution
Modification of transcribed mRNAs enables regulation of transcription but its extent in cancer cells is incompletely understood. Here, the authors analyse transcript assembly in over 1000 cancer cell lines and find unannotated transcripts are common, and are associated with drug sensitivity.
- Wei Hu
- , Yangjun Wu
- & Shengli Li
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Article
| Open AccessSingle-cell profiling reveals a memory B cell-like subtype of follicular lymphoma with increased transformation risk
Follicular lymphoma can transform to a more aggressive histology. Here, the authors use bulk and single cell analysis to create a 26 marker panel which could be used to profile FL samples and predict the risk of transformation using flow cytometry.
- Xuehai Wang
- , Michael Nissen
- & Andrew P. Weng
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| Open AccessSpatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival
Characterisation of molecular heterogeneity in glioblastoma would improve patient stratification. Here, the authors integrate spatial proteomics and clinical data from glioblastoma patients and identify 3 molecular groups and a 5-protein signature that was associated with survival.
- Marie Duhamel
- , Lauranne Drelich
- & Michel Salzet
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| Open AccessCollaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer
The Bladder Cancer Advocacy Network established the UC-GENOME study in order to create a biobank and data repository for metastatic urothelial carcinoma. Here, the authors present the first characterization and analysis of DNA and RNA sequencing data from the 218 patients included in the UC-GENOME.
- Jeffrey S. Damrauer
- , Wolfgang Beckabir
- & Matthew I. Milowsky
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Article
| Open AccessFOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation
Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity.
- Joshua I. Warrick
- , Wenhuo Hu
- & Hikmat A. Al-Ahmadie
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Article
| Open AccessFOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis
Forkhead box transcription factor, FOXQ1 is reported to promote epithelial-mesenchymal transition (EMT) and cancer metastasis. Here the authors show that FOXQ1 recruits the KMT2/MLL histone methyltransferase complex as a transcriptional coactivator to activate EMT programme in breast cancer.
- Allison V. Mitchell
- , Ling Wu
- & Guojun Wu
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Article
| Open AccessMIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia
The links between DNA methylation and gene expression are poorly understood on large-scale. Here the authors show that MIR retrotransposons within introns can play this role in acute myeloid leukemia harbouring mutations in epigenetic modifiers.
- Aristeidis G. Telonis
- , Qin Yang
- & Maria E. Figueroa
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Article
| Open AccessTargeting vasoactive intestinal peptide-mediated signaling enhances response to immune checkpoint therapy in pancreatic ductal adenocarcinoma
Poor antitumor response of pancreatic cancer to immunotherapies is a major barrier to effective disease management. Herein we show that pancreatic cancers overexpress vasoactive intestinal peptide, and pharmacological inhibition of its signaling significantly enhances responsiveness of pancreatic ductal adenocarcinoma to immune checkpoint therapy, thus improving overall survival in mouse models.
- Sruthi Ravindranathan
- , Tenzin Passang
- & Edmund K. Waller
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Article
| Open AccessClonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma. Here we show that identification of clonal somatic copy number alterations in frequently amplified cancer genes could inform therapeutics for precision medicine.
- Filipe Correia Martins
- , Dominique-Laurent Couturier
- & James D. Brenton
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Article
| Open AccessEnhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response
Activation of ESCRT-mediated cell membrane repair can reduce the extent of tumor cell pyroptosis. Here the authors develop two formulations (an injectable hydrogel and a cell patch) for the sustained release of a Gasdermin-D bacteria-based delivery system and of biodegradable nanoparticles loaded with an ESCRT inhibitor, triggering pyroptosis and antitumor immune responses in preclinical cancer models.
- Zhaoting Li
- , Fanyi Mo
- & Quanyin Hu
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Article
| Open AccessPD-L1-directed PlGF/VEGF blockade synergizes with chemotherapy by targeting CD141+ cancer-associated fibroblasts in pancreatic cancer
A desmoplastic stroma, enriched in cancer-associated fibroblasts (CAF), has been associated with resistance to therapy in patients with pancreatic ductal adenocarcinoma (PDAC). Here, after showing that chemotherapy promotes tumor fibrosis by increasing CAF frequency and activity, the authors develop a multi-paratopic VEGF decoy receptor for PD-L1 directed PlGF/VEGF blockade, promoting anti-fibrotic and anti-tumor effects in PDAC models.
- Duk Ki Kim
- , Juhee Jeong
- & Keehoon Jung
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Article
| Open AccessA phase II trial of weekly nab-paclitaxel for progressive and symptomatic desmoid tumors
In patients with progressive and symptomatic desmoid fibromatosis (DF) treatment with chemotherapy is typically prolonged, while surgery carries a high risk of relapse. Here, the authors report the results of a phase II clinical trial of short-course nab-paclitaxel in patients with progressive and symptomatic DF.
- Javier Martin-Broto
- , Andres Redondo
- & Nadia Hindi
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| Open AccessViral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape
NOTCH mutations are frequent in B cell malignancies. Here the authors use retroviral transduction of primary malignant B cells from Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) patients to show that NOTCH1/2-mutations facilitate mechanism of immune escape.
- Maurizio Mangolini
- , Alba Maiques-Diaz
- & Ingo Ringshausen
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| Open AccessReprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma
Myeloid cells contribute to the tumor microenvironment of thyroid cancers, but their functional relevance is lesser known. Here authors show that myeloid cells infiltrating non-medullary thyroid carcinomas upregulate their antigen presentation-related genes, release less cytokines and over-produce reactive oxygen species, with transcriptional changes already present in extra-tumoral myeloid cells.
- Katrin Rabold
- , Martijn Zoodsma
- & Romana T. Netea-Maier
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Article
| Open AccessComprehensive and clinically accurate head and neck cancer organs-at-risk delineation on a multi-institutional study
Accurate organ at risk (OAR) segmentation is critical to reduce the radiotherapy post-treatment complications. Here, the authors develop an automated OAR segmentation system to delineate a comprehensive set of 42 H&N OARs.
- Xianghua Ye
- , Dazhou Guo
- & Tsung-Ying Ho
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Article
| Open AccessHSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia
Acute myeloid leukaemia (AML) is maintained by self-renewing leukemic stem cells. Here the authors show that Heat Shock Transcription Factor 1 (HSF1) is specifically required for the maintenance of AML stem cells, while sparing steady-state and stressed haematopoiesis and that pharmacologically targeting HSF1 may have broad anti-leukemic effects.
- Qianze Dong
- , Yan Xiu
- & Chen Zhao
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| Open AccessFibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system
Fibrocytes are monocyte-derived cells implicated in wound healing. Here, the authors utilise single cell RNA-seq, genetic ablation and multiplexed imaging to identify a fibrocyte population in lung cancer models, and use human lung cancer coculture systems to highlight their potential to modulate microenvironmental niche and sensitivity to endothelin blockade.
- Andreas Weigert
- , Xiang Zheng
- & Rajkumar Savai
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| Open AccessA single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer
In patients with advanced gastric cancer (AGC), resistance to treatment with trastuzumab and cytotoxic chemotherapy remains high. Here, the authors report the results of a phase Ib/II clinical trial assessing the safety and clinical response to a quadruplet regimen of pembrolizumab, trastuzumab, capecitabine, and cisplatin as a first-line therapy for HER2-positive AGC.
- Choong-kun Lee
- , Sun Young Rha
- & Hyun Cheol Chung
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| Open AccessDifferential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors
Patients treated with Aurora kinase inhibitors experience dose-limiting neutropenia while other cytopenias are rare. Here, Chou et al. show that this cell-type specific side effect is partly explained by loss of drug efflux pump expression during neutrophil differentiation.
- David B. Chou
- , Brooke A. Furlong
- & Donald E. Ingber
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Article
| Open AccessEvolution and modulation of antigen-specific T cell responses in melanoma patients
Previous studies have characterized the diversity and dynamics of the T cell receptor (TCR) repertoire in patients with solid cancer. Here, by analyzing TCR repertoire data from multiple datasets, the authors report that melanoma-associated antigen-specific TCRs can be used to separate metastatic melanoma patients from healthy controls and to follow anti-tumor responses in patients treated with immunotherapy.
- Jani Huuhtanen
- , Liang Chen
- & Satu Mustjoki
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| Open AccessMolecular characterization of renal cell carcinoma tumors from a phase III anti-angiogenic adjuvant therapy trial
Based on the S-TRAC results, sunitinib is approved as adjuvant treatment for adult patients at high risk of recurrent RCC following nephrectomy. Here, the authors report the results of an integrated multi-omics tumor analysis of 171 patients from the trial and identify specific molecular subtypes as well as potential new targets.
- Robert J. Motzer
- , Jean-François Martini
- & Alain Ravaud
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| Open AccessIntegrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma
KRAS wildtype metastatic pancreatic ductal adenocarcinoma (mPDAC) could represent a distinct molecular entity from other PDACs. Here, the authors analyse KRAS wildtype mPDAC tumours using genomics and transcriptomics and find molecular similarities with cholangiocarcinomas.
- James T. Topham
- , Erica S. Tsang
- & Daniel J. Renouf
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| Open AccessZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer
Cancer-associated fibroblasts (CAFs) have been implicated in lung cancer chemo-resistance. Here the authors show that a zinc-transporter positive CAF subset is enriched in lung cancer models after chemotherapy and actively transfers zinc to cancer cells, promoting ABCB1-mediated chemo-resistance.
- Chen Ni
- , Xiaohan Lou
- & Zhihai Qin
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Article
| Open AccessIntegrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance
Human papillomavirus (HPV) is a known cause of cervical cancer. Here, the authors perform a multi-omic analysis using published cervical squamous cell carcinoma cohorts from the USA, Europe, and SubSaharan Africa and identify two cervical squamous cell carcinoma subtypes that display prognostic differences.
- Ankur Chakravarthy
- , Ian Reddin
- & Tim R. Fenton
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| Open AccessThe design and evaluation of hybrid controlled trials that leverage external data and randomization
Patient-level external control data from prior clinical studies or electronic health records can be used in the design and analysis of clinical trials. Here the authors report a hybrid trial design combining the use of external control data and randomization to test experimental treatments, using small cell lung cancer and glioblastoma datasets as examples.
- Steffen Ventz
- , Sean Khozin
- & Lorenzo Trippa
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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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| 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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| 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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| 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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| 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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| 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