Featured
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| Open AccessTargeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBPα activation as a mechanism of FLT3i resistance and therapeutically target C/EBPα activation in combination with FLT3i in preclinical models FLT3-ITD AML.
- Hanlin Wang
- , Guanghao Luo
- & Jia Li
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Article
| Open AccessEtiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication
Oncogenic gene fusions are frequent in childhood cancers but remain poorly understood and untargeted. Here, the authors identify 272 oncogenic fusions in transcriptomics data from 5190 childhood cancer patients, revealing their possible etiologies, their links with tumor progression and evolution, and their potential as therapeutic targets.
- Yanling Liu
- , Jonathon Klein
- & Xiaotu Ma
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Article
| Open AccessAn epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma
Melanocytes can de-differentiate into neural crest cell (NCC)- like states during metastatic melanoma progression. Here the authors compare DNA methylation profiles of NCCs and melanocytes, as well as primary and metastatic patient tissues and identify that DNA methylation changes of NR2F2 isoform 2 influence cell state transitions and melanoma metastatic spread.
- Veronica Davalos
- , Claudia D. Lovell
- & Eva Hernando
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Article
| Open AccessMonocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma
Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.
- Zhihong Chen
- , Nishant Soni
- & Dolores Hambardzumyan
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Article
| Open AccessSmad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma
TGF-β stimulated tumor-associated neutrophils (TANs) can exert pro-tumoral functions. Here the authors show that Smad3 activation in TANs is associated with an N2-like polarization state and poor outcome in patients with non-small cell lung carcinoma and that Smad3 targeting reprograms TANs to an antitumor state suppressing tumor growth in preclinical lung cancer models.
- Jeff Yat-Fai Chung
- , Philip Chiu-Tsun Tang
- & Patrick Ming-Kuen Tang
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Article
| Open AccessAn actin filament branching surveillance system regulates cell cycle progression, cytokinesis and primary ciliogenesis
The authors find that the ciliopathy-associated protein Oral-Facial-Digital syndrome 1 functions as a class II nucleation promoting factor to drive actin filament branching, required for cell cycle progression. Interferring with this function suppresses cancer cell growth.
- Muqing Cao
- , Xiaoxiao Zou
- & Qing Zhong
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Article
| Open AccessClonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia
High hyperdiploid acute lymphoblastic leukaemia (HeH ALL) is driven by nonrandom chromosomal gains, which have been suggested to arise early - even before birth. Here, the authors use single-cell whole genome sequencing and in silico modelling to show that HeH ALL aneuploidies could originate early and follow punctuated evolution.
- Eleanor L. Woodward
- , Minjun Yang
- & Kajsa Paulsson
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Article
| Open AccessGenomic characterization of DICER1-associated neoplasms uncovers molecular classes
DICER1 syndrome is associated with a predisposition to multiple tumor types. Here, the authors identify and characterize 3 molecular subgroups of mesenchymal tumors with DICER1 mutations.
- Felix K. F. Kommoss
- , Anne-Sophie Chong
- & William D. Foulkes
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Article
| Open AccessSTING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma
Glioblastoma is an immunologically cold tumour, with poor CD8 + T cell infiltration and enrichment in immunosuppressive tumour-associated myeloid cells. Here, the authors generate a bispecific lipid nanoparticle targeting CD47 and PD-L1, combined with a STING agonist, to promote anti-tumour immunity.
- Peng Zhang
- , Aida Rashidi
- & Maciej S. Lesniak
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Article
| Open AccessCheckpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade
Immunotherapies have shown limited efficacy in patients with glioma. Here, based on an in vivo kinome knockout CRISPR screen, the authors show that checkpoint kinase 2 promotes CD8 T cell immune evasion and that its depletion or inhibition improve survival and response to PD1/PDL1 blockade in preclinical glioma models.
- Crismita Dmello
- , Junfei Zhao
- & Adam M. Sonabend
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Article
| Open AccessSynthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma
Genomic instability occurs infrequently in in diffuse large B cell lymphoma (DLBCL), suggesting a therapeutic vulnerability. Here, the authors identify a synergistic combination between the induction of polyploidy by a PLK4 inhibitor and a BCL-2 inhibitor in DLBCL.
- Ana Portelinha
- , Mariana da Silva Ferreira
- & Hans-Guido Wendel
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Article
| Open AccessCumulative burden of 144 conditions, critical care hospitalisation and premature mortality across 26 adult cancers
Here the authors evaluate the burden of 144 health conditions in adult cancer survivors, and show that the magnitude of late morbidities experienced by survivors varies according to the type of cancer and treatment, highlighting opportunities for optimising patient care
- Wai Hoong Chang
- , Richard D. Neal
- & Alvina G. Lai
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Article
| Open AccessIntegrated transcriptome study of the tumor microenvironment for treatment response prediction in male predominant hypopharyngeal carcinoma
Many patients with hypopharyngeal carcinoma (HPC) do not respond to first-line combination therapy. Here, the authors analyse the tumour and the tumour microenvironment of HPC patients treated with combination therapy using single-cell RNA-seq, and train a classifier to distinguish responders based on cell type composition.
- Yang Zhang
- , Gan Liu
- & Zhigang Huang
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Article
| Open AccessClinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma
Treatment options in patients with recurrent endometrial carcinoma (EC) are limited and response rates to chemotherapy are poor. Here the authors report the results of a phase II trial of niraparib (PARP inhibitor) monotherapy or in combination with dostarlimab (anti-PD1) in recurrent EC.
- Ainhoa Madariaga
- , Swati Garg
- & Stephanie Lheureux
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Article
| Open AccessBET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas
Bromodomain and extraterminal proteins (BET) are reported as targets for anticancer therapy. Here, the authors report the final results of a phase I clinical trial of the BET inhibitor trotabresib in patients with solid tumours and diffuse large B-cell lymphoma.
- Victor Moreno
- , Maria Vieito
- & Irene Braña
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Article
| Open AccessRETRACTED ARTICLE: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer
Polymerase (POL) θ inhibitors display synthetic lethality in tumours with homologous recombination repair deficiency. Here, the authors demonstrate that POLθ inhibition with novobiocin activates the cGAS/STING pathway in BRCA-deficient cancers.
- Jeffrey Patterson-Fortin
- , Heta Jadhav
- & Geoffrey I. Shapiro
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Article
| Open AccessRecapitulating thyroid cancer histotypes through engineering embryonic stem cells
Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. Here, the authors show the ability of human embryonic stem cells (hESCs) to recapitulate the different TC histotypes upon specific genomic alterations delivered by CRISPR-Cas9 and identify KISS1R and TIMP1 targeting as a therapeutic adjuvant option for undifferentiated TCs.
- Veronica Veschi
- , Alice Turdo
- & Giorgio Stassi
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Article
| Open AccessClinical and biomarker analyses of sintilimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced biliary tract cancer
Chemotherapeutic agents and immune checkpoint inhibitors have shown modest efficacy in patients with advanced biliary tract cancers (BTCs). Here the authors report the results of a phase II trial of the anti-PD1 antibody sintilimab plus chemotherapy (gemcitabine and cisplatin) as first-line treatment for patients with advanced BTCs.
- Tian-mei Zeng
- , Guang Yang
- & Zhen-gang Yuan
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Article
| Open AccessThe TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma
TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.
- Lucia Morgado-Palacin
- , Jessie A. Brown
- & Adolfo A. Ferrando
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Article
| Open AccessLYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1
The survival of chronic lymphocytic leukemia cells strongly depends on the presence of a supportive microenvironment. Here, the authors show that LYN kinase is essential for the reprogramming of stromal cells towards a leukemia-supportive phenotype that facilitates disease progression.
- Alexander F. vom Stein
- , Rocio Rebollido-Rios
- & Michael Hallek
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Article
| Open AccessLongitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia
Relapse within acute myeloid leukaemia may be driven by the presence of leukaemia stem cells. Here, the authors use single cell RNA-seq seq to characterise leukemia stem cells, and show miR-126 as a potential marker of resistance.
- Matteo Maria Naldini
- , Gabriele Casirati
- & Bernhard Gentner
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Article
| Open AccessNon-canonical functions of SNAIL drive context-specific cancer progression
SNAIL promotes tumour metastasis through inducing epithelial to mesenchymal transition (EMT). Here the authors report that SNAIL bypasses senescence and regulates cell cycle progression to promote pancreatic carcinogenesis and this is independent of EMT induction.
- Mariel C. Paul
- , Christian Schneeweis
- & Dieter Saur
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Article
| Open AccessARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
CDKN2A loss and p53 mutations are rare in MYC-driven Group 3 medulloblastomas (MBs). Here the authors generated a transgenic mouse model of Group 3 MB by MYC overexpression and show that MYC suppresses ARF to drive tumorigenesis.
- Oliver J. Mainwaring
- , Holger Weishaupt
- & Fredrik J. Swartling
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Article
| Open AccessmTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion
B7-H3 is expressed at high levels in several cancer types and can suppress antitumor immune responses. Here the authors show that B7-H3 expression is dependent on mTORC1 activity and that inhibition of B7-H3 promotes antitumor immunity mediated by cytolytic CD4 + T cells in tumor models with mTORC1 hyperactivity.
- Heng-Jia Liu
- , Heng Du
- & Elizabeth P. Henske
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Article
| Open AccessCirculating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer
Plasma ctDNA is a promising method to determine patient outcome in multiple cancer types. Here, the authors use shallow WGS to create machine learning signatures to identify tumor phenotypes and predict therapy response in patients with metastatic breast cancer.
- Aleix Prat
- , Fara Brasó-Maristany
- & Ana Vivancos
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Article
| Open AccessCandidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer
In the phase III FLAURA study (NCT02296125), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib provided superior progression-free survival versus comparator EGFR-TKIs in patients with NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to first-line osimertinib in patients from the FLAURA trial.
- Juliann Chmielecki
- , Jhanelle E. Gray
- & Suresh S. Ramalingam
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| Open AccessAnalysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial
In the phase III AURA3 study (NCT02151981), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor osimertinib prolonged progression-free survival versus platinum-doublet chemotherapy in patients with EGFR T790M advanced NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to osimertinib in patients from the AURA3 trial.
- Juliann Chmielecki
- , Tony Mok
- & Vassiliki Papadimitrakopoulou
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Article
| Open AccessSpatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas
The spatial organisation of diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) remains to be investigated. Here, the authors integrate short-read and long-read spatial profiling of DMG and GBM to identify regulatory programs and cellular ecosystems in distinct glioma niches.
- Yanming Ren
- , Zongyao Huang
- & Yuan Wang
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Article
| Open AccessNoncanonical amino acids as doubly bio-orthogonal handles for one-pot preparation of protein multiconjugates
Site-specific protein multi-conjugates are important for both scientific and translational research. Here, the authors genetically encode unnatural amino acids which contain both tetrazine and azide, and use the doubly bio-orthogonal handles to generate bi- and tri-conjugate proteins in high yields.
- Yong Wang
- , Jingming Zhang
- & Tao Liu
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Article
| Open AccessA nitric-oxide driven chemotactic nanomotor for enhanced immunotherapy of glioblastoma
The blood-brain barrier represents a hurdle for the delivery of therapeutics in brain tumor tissues. Here the authors describe the design of a nitric oxide-driven nanomotor loaded with the glycolysis inhibitor lonidamine, breaking through the blood-brain barrier and eliciting anti-tumor immune responses in preclinical models of glioblastoma.
- Huan Chen
- , Ting Li
- & Mimi Wan
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Article
| Open AccessTracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing
It is essential to understand heterogeneity and evolution at different omics levels in oesophageal squamous cell carcinoma (ESCC). Here, the authors use multi-omics to analyse heterogeneity and evolution in ESCC patient samples, and characterise the levels of immune infiltration as well as selective pressure from the tumour microenvironment.
- Sijia Cui
- , Nicholas McGranahan
- & Shixiu Wu
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Article
| Open AccessThe ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome
The identification of kinases that control epigenetic mechanisms in squamous cell carcinomas (SCCs) can be of therapeutic relevance. Here the authors show that loss of nuclear kinase ULK3 impairs the recruitment of two histone arginine methyltransferases, PRMT1 and PRMT5 to the promoter regions of genes of functions, hence, suppressing the tumorigenic potential of SCC cells.
- Sandro Goruppi
- , Andrea Clocchiatti
- & G. Paolo Dotto
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Article
| Open AccessCoadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) cells can utilise the tumour microenvironment to metastasise to the liver. Here the authors show that hepatoctyes overexpress SLIT2 to enable premetastatic niche formation for ROBO1-positive PDAC cells to support the survival of these tumour cells in the liver.
- Qing Li
- , Xiao-Xin Zhang
- & Zhi-Gang Zhang
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Article
| Open AccessSingle-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis
Peritoneal metastasis is one of the most common forms of death for gastrointestinal cancers, however, its cell composition is incompletely understood. Here, the authors use single cell RNA-seq of peritoneal metastases from 35 patients and show diversity in immune cells, and plasticity in cancer cell phenotypes and autophagy related genes as biomarkers of prognosis.
- Xuan-Zhang Huang
- , Min-Jiao Pang
- & Zhen-Ning Wang
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Article
| Open AccessMultilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer
The molecular differences between the two major gastric cancer subtypes diffuse-type gastric cancer (DGC) and intestinaltype gastric cancer (IGC) remain to be investigated. Here, integrated analysis of proteome, phospho-proteome and transcription factor activity for DGC and IGC reveals potential subtypes.
- Wenhao Shi
- , Yushen Wang
- & Chen Ding
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Article
| Open AccessSingle-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
The role of therapy in shaping the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) remains to be explored. Here, the authors perform single-cell RNA sequencing in PDAC samples before and after chemotherapy and suggest that chemotherapy may promote resistance to immunotherapy.
- Gregor Werba
- , Daniel Weissinger
- & Diane M. Simeone
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Article
| Open AccessIntegrative proteomic characterization of adenocarcinoma of esophagogastric junction
The molecular subtypes of adenocarcinoma of the esophagogastric junction (AEG) remain to be identified. Here, the authors perform proteogenomic characterisation of AEG tumours with paired normal adjacent tissues and suggest three proteomic subtypes and potential druggable targets.
- Shengli Li
- , Li Yuan
- & Xiang-Dong Cheng
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Article
| Open AccessFGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells
Glioblastoma is an aggressive type of cancer with poor patient prognosis. Here, the authors show that T cells armed with an FGL2-specific scFV can induce antitumour responses mediated by tissue-resident memory T cells in the brain.
- Qingnan Zhao
- , Jiemiao Hu
- & Shulin Li
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Article
| Open AccessLong-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.
- Jenniffer Linares
- , Anna Sallent-Aragay
- & Alexandre Calon
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Article
| Open AccessBile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer
Non-enterotoxigenic Bacteroides fragilis (NTBF) is abundant in colorectal cancer (CRC) patients and in a high-fat diet (HFD)-induced CRC model. Here the authors show that bile salt hydrolase-expressing NTBF is enriched in CRC patients with overweight and promotes tumor growth in an HFD-induced CRC mouse model.
- Lulu Sun
- , Yi Zhang
- & Frank J. Gonzalez
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Article
| Open AccessLoss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability
Group 3 medulloblastomas (MBs) have the worst prognosis amongst the subtypes of MBs and are associated with MYC amplifications. Here the authors identify that mutations in CTDNEP1 cause MYC activation, amplification, and genomic instability in this subtype of MBs.
- Zaili Luo
- , Dazhuan Xin
- & Q. Richard Lu
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Article
| Open AccessMitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells
DNA replication stress can generate under-replicated DNA regions which is fixed by an atypical form of DNA repair synthesis in mitosis (MiDAS). Here the authors show that translesion and replicative DNA polymerases cooperate via the POLD3 subunit to complete MiDAS in human cells.
- Wei Wu
- , Szymon A. Barwacz
- & Ying Liu
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Article
| Open AccessEfficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer
Immune checkpoint inhibitors with or without chemotherapy are now standard of care for non-small cell lung cancer. However, the benefits of combination vs sequential therapy have not been fully explored. Here, the authors analysed 1,133 patient records and show combination therapy showed increased protection against early progression, but similar overall survival.
- Lingzhi Hong
- , Muhammad Aminu
- & Natalie I. Vokes
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Article
| Open AccessAntitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers
In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.
- James J. Harding
- , Sarina A. Piha-Paul
- & Ghassan K. Abou-Alfa
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Article
| Open AccessEstablishment and validation of a plasma oncofetal chondroitin sulfated proteoglycan for pan-cancer detection
Developing multi-cancer early detection (MCED) tests based on cfDNA or protein markers holds great promise for effective cancer screening. Here, the authors show a sensitive, non-invasive pan-cancer detection method that concurrently detects the oncofetal chondroitin sulfate (ofCS) glycans and its protein backbone in plasma.
- Pei-Fen Zhang
- , Zi-Yi Wu
- & Wei-Hua Jia
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Comment
| Open AccessEpigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer
Prostate cancer is a highly heterogeneous disease. Progression on androgen deprivation therapy (ADT) to castration-resistant (CRPC), or neuroendocrine prostate cancer (NEPC), is associated with poor patient survival. This comment highlights recent evidence on the epigenetic mechanisms underlying the emergence of lineage plasticity and neuroendocrine differentiation in treatment-resistant prostate tumors.
- Goutam Chakraborty
- , Kasmira Gupta
- & Natasha Kyprianou
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Article
| Open AccessDeletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy
The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.
- Marcel P. Trefny
- , Nicole Kirchhammer
- & Alfred Zippelius
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Article
| Open AccessGermline T cell receptor exchange results in physiological T cell development and function
The currently available transgenic T cell receptor (TCR) models represent high affinity antigen-TCR interactions. Authors here present an alternative approach to target an exogenous TCR into the physiological Trac locus in the germline of mice, which uncovers that the natural genomic context for TCRs can enhance the antigen sensitivity of lower affinity TCRs and enables the physiologic range of antigen-TCR interaction and a gene dosage dependent mechanism of central tolerance.
- Meagan R. Rollins
- , Jackson F. Raynor
- & Ingunn M. Stromnes
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Comment
| Open AccessA two-faced selectivity solution to target SMARCA2 for cancer therapy
Two new studies exploring PROTAC-mediated degradation of SMARCA2 for cancer therapy solve an apparently intractable selectivity challenge with SMARCA4 by utilising the requirement for a productive ternary complex between the protein, PROTAC and ligase complex.
- John D. Harling
- & Christopher P. Tinworth