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Article
| Open AccessMesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR
Vasectasia is a newly described, non-angiogenic form of blood vessel formation induced by mesenchymal glioblastoma cells, and driven by endothelial cell responses to extracellular vesicles containing oncogenic EGFR.
- Cristiana Spinelli
- , Lata Adnani
- & Janusz Rak
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Article
| Open AccessLoss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment
CREBBP and KMT2D mutations frequently co-occur in B cell lymphomas with unclear significance. Here the authors show that they cooperate to skew B cell fate decisions and induce a CD8-depleted immune-evasive microenvironment to facilitate lymphomagenesis.
- Jie Li
- , Christopher R. Chin
- & Ari M. Melnick
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Article
| Open AccessSpatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones
Intratumoural heterogeneity in high-grade serous ovarian carcinoma (HGSOC) remains to be explored. Here, the authors perform spatial transcriptomics and reveal a high degree of subclonal heterogeneity in HGSOC.
- Elena Denisenko
- , Leanne de Kock
- & Alistair R. R. Forrest
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Article
| Open AccessTargeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade
Cancer cells can employ aberrant glycosylation patterns to evade the host immune response. Here the authors report that inhibition of branched N-glycans sensitizes homologous recombination (HR)-proficient, but not HR-deficient, epithelial ovarian cancer to immune checkpoint inhibitors.
- Hao Nie
- , Pratima Saini
- & Rugang Zhang
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Article
| Open AccessObesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk
Obesity represents a risk factor for cancer and compromises immune function, however the mechanisms linking the two together are not fully known. Here authors show in a mouse sarcoma model that obesity increases tumour incidence, impairs intra-tumoral T cell immunity but paradoxically increases sensitivity to immune therapy via impairing immunoediting.
- Alexander Piening
- , Emily Ebert
- & Ryan M. Teague
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Article
| Open AccessDeciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
The heterogeneity of cancer associated fibroblasts (CAFs) in breast cancer has been previously described. Here the authors provide further insights into the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
- Hugo Croizer
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessCD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer
Tumor associated macrophages (TAM) are playing an active role in tumor immune evasion in multiple cancer type. Here authors show that CD276 expression by TAMs may underpin this immune-suppressive role via promoting efferocytosis and suppressing MHC class II expression, which result in decreased CD4+ and CD8 + T cell infiltration.
- Maosheng Cheng
- , Shuang Chen
- & Liang Peng
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Article
| Open AccessSystematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma
Proteomic, transcriptomic, and genomic analysis has shown osteosarcoma (OS) to be a complex and heterogenous disease but revealed little about its carcinogenesis or potential therapeutic targets. Here, the authors profile the RNA interactome, transcriptome and proteome of cells derived from OS patients, identifying a targetable vulnerability to translation inhibition.
- Yang Zhou
- , Partho Sarothi Ray
- & Andreas E. Kulozik
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Article
| Open Accessp53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
Here the authors uncover p53’s role as the master regulator of spatio-temporal genome organization. p53 controls the expression of 340 distal genes through newly formed and pre-existing loops between p53-bound enhancers and promoters.
- François Serra
- , Andrea Nieto-Aliseda
- & Biola M. Javierre
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Article
| Open AccessCombination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial
Potential synergism between BTK inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab in patients with aggressive Relapsed/Refractory aggressive B-cell non-Hodgkin lymphoma.
- Changhee Park
- , Ho Sup Lee
- & Youngil Koh
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Article
| Open AccessThe CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.
- Elena Giudice
- , Tzu-Ting Huang
- & Jung-Min Lee
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Article
| Open AccessMyeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies
Myeloid derived suppressor cells (MDSC) are associated with tumourigenesis and therapy response. Here, the authors show that beta 2-adrenergic receptor activation in MDSC leads to metabolic rewiring which regulates chemotherapy response in preclinical models of blood cancer.
- Saeed Daneshmandi
- , Jee Eun Choi
- & Hemn Mohammadpour
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Article
| Open AccessIdentification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms
The current stratification of Intraductal Papillary Mucinous Neoplasms (IPMN) is based on clinical and histological features rather than molecular ones. Here, the authors use spatial transcriptomics to characterise IPMN patient samples, and identify markers associated with progression to pancreatic cancer.
- Antonio Agostini
- , Geny Piro
- & Carmine Carbone
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Article
| Open AccessNanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer
In non-small cell lung cancer (NSCLC), inactivating p53 mutations can drive resistance to cisplatin. Here, the authors develop fluplatin nanoparticles comprising a prodrug of cisplatin and fluvastin (mutant p53 inhibitor) which selectively degrades mutant p53, prevent tumor recurrences in preclinical models of p53 mutant NSCLC.
- Yu-Yang Bi
- , Qiu Chen
- & Hu-Lin Jiang
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Article
| Open AccessCell surface patching via CXCR4-targeted nanothreads for cancer metastasis inhibition
CXCR4-targeted therapies have been proposed for the treatment of cancer metastasis. Here the authors propose a CXCR4-targeted strategy based on interactable polymer nanothreads, showing inhibition of metastasis in preclinical cancer models.
- Minglu Zhou
- , Chendong Liu
- & Lian Li
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Article
| Open AccessComprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants
EGFR mutations are frequent in glioblastoma and lung cancer. Here, the authors perform deep mutational scanning of EGFR, followed by a high-throughput functional screen and analysis of patient data, to identify variants with differing sensitivities to a range of EGFR tyrosine kinase inhibitors.
- Tikvah K. Hayes
- , Elisa Aquilanti
- & Matthew Meyerson
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Article
| Open AccessSpiDe-Sr: blind super-resolution network for precise cell segmentation and clustering in spatial proteomics imaging
Imaging mass cytometry (IMC) is a powerful single-cell resolution platform for targeted spatial proteomics, but it can be constrained by imaging noise and resolution. Here, the authors propose SpiDe-Sr, a super-resolution network embedded with a denoising module for IMC spatial resolution enhancement.
- Rui Chen
- , Jiasu Xu
- & Xianting Ding
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Article
| Open AccessAdjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study
Post-neoadjuvant treatment options for patients with triple-negative breast cancer (TNBC) include the chemo-drug capecitabine but also immune checkpoint inhibitors. Here the authors report the results of a phase II study of adjuvant nivolumab, capecitabine or the combination in patients with residual TNBC.
- Filipa Lynce
- , Candace Mainor
- & Claudine Isaacs
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Article
| Open AccessDevelopment and validation of an interpretable model integrating multimodal information for improving ovarian cancer diagnosis
Ovarian cancer diagnosis can be complex and can be improved through integration of multimodal data. Here, the authors develop OvcaFinder which can significantly outperform clinical models using ultrasound images and known clinical characteristics.
- Huiling Xiang
- , Yongjie Xiao
- & Hao Chen
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Perspective
| Open AccessExpected and unexpected effects after systemic inhibition of Hippo transcriptional output in cancer
Hyperactivation of YAP/TAZ, the Hippo pathway downstream effectors, is common in human cancer. In this perspective, the authors review the role of the Hippo pathway in distinct tumor cell populations, discuss the impact of inhibiting Hippo output on tumor growth, and examine current developments in YAP/TAZ inhibitors.
- Isabel Baroja
- , Nikolaos C. Kyriakidis
- & Iván M. Moya
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Article
| Open AccessPolygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis
Colitis is one of the most common immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors. Here the authors show that a polygenic risk score for ulcerative colitis can predict immune checkpoint inhibitor-mediated colitis in patients with cancer.
- Pooja Middha
- , Rohit Thummalapalli
- & Elad Ziv
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Article
| Open AccessPhenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers
Mendelian randomisation can identify potential risk factors from large populations. Here, the authors analyse 3000 traits across multiple cancer types to search for potential risk factors and molecular biomarkers.
- Molly Went
- , Amit Sud
- & Richard Houlston
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Article
| Open AccessOutcome differences by sex in oncology clinical trials
The role of sex differences in response to cancer therapy remains unclear but this could be improved by reporting sex comparisons of outcomes in clinical trials. Here, the authors characterise the sex outcome comparisons in 89,221 interventional trials, finding that while comparisons were rare, important insights could be obtained.
- Ashwin V. Kammula
- , Alejandro A. Schäffer
- & Eytan Ruppin
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Article
| Open AccessFANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells
Here the authors show that PARPi efficacy along with the fitness of BRCA1 deficient cells relies on FANCJ, which maintains S-phase PARP1 activity by preventing its sequestration with MSH2 on G-quadruplexes.
- Ke Cong
- , Nathan MacGilvary
- & Sharon B. Cantor
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Article
| Open AccessCancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma
Distinct genetic mutations can shape the tumor immune microenvironment. Here the authors generate preclinical mouse models of hepatocellular carcinoma bearing clinically-relevant oncogenic driver combinations, identifying myeloid cell-centric exploitable therapeutic vulnerabilities.
- Christel F. A. Ramirez
- , Daniel Taranto
- & Leila Akkari
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Article
| Open AccessMultipeptide vaccines for melanoma in the adjuvant setting: long-term survival outcomes and post-hoc analysis of a randomized phase II trial
Peptide-based cancer vaccines require epitopes for both CD8+ and CD4+ T cells. Here the authors report the long-term outcomes of a randomized phase II trial (NCT00118274) in patients with melanoma designed to evaluate a class I MHC-restricted peptide vaccine plus one of two “helper” peptide preparations to stimulate CD4+ T cells, either non-specific help or melanoma-specific help.
- Emily K. Ninmer
- , Hong Zhu
- & Craig L. Slingluff Jr
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Article
| Open AccessBET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3
Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Francesca Reggiani
- , Giovanna Talarico
- & Valentina Sancisi
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Article
| Open AccessSingle cell deciphering of progression trajectories of the tumor ecosystem in head and neck cancer
Head and neck squamous cell carcinoma (HNSCC) is characterised with high heterogeneity and unfavourable prognosis. Here, the authors perform single cell transcriptomics to investigate the tumour microenvironment features of HNSCC initiation, progression, lymph node metastasis and recurrence.
- Z. L. Liu
- , X. Y. Meng
- & Y. He
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Article
| Open AccessSpatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Spatial positioning of cells within the tumour microenvironment may have a function in the success of immune checkpoint immunotherapy (ICI). Here the authors analyse spatial relationships from immunohistochemistry samples prior to ICI therapy and show that CD8 T cell or macrophage proximity to cancer cells is associated with better responses.
- Alberto Gil-Jimenez
- , Nick van Dijk
- & Lodewyk F. A. Wessels
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Article
| Open AccessThe EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression
Eukaryotic initiation translation factor 3 subunit h (EIF3H) possesses an alternative “moonlighting” function of deubiquitinase, while its role in colorectal carcinogenesis remains to be explored. Here the authors show that EIF3H deubiquitinates and stabilizes HAX1, which enhances RAF-MEK-ERK signaling to promote colorectal tumor growth and metastasis.
- Huilin Jin
- , Xiaoling Huang
- & Mong-Hong Lee
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Article
| Open AccessTertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer
Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.
- Lenka Kasikova
- , Jana Rakova
- & Jitka Fucikova
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Article
| Open AccessAberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma
The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression.
- Daniel A. Ang
- , Jean-Michel Carter
- & Yinghui Li
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Article
| Open AccessGAS41 modulates ferroptosis by anchoring NRF2 on chromatin
GAS41 is recognized as a histone reader and oncogene, but the mechanism by which GAS41 contributes to tumorigenesis is not well understood. Here, the authors discover that GAS41 is a ferroptosis repressor that anchors NRF2 to chromatin, promoting tumor growth.
- Zhe Wang
- , Xin Yang
- & Wei Gu
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Article
| Open AccessOxygen-independent organic photosensitizer with ultralow-power NIR photoexcitation for tumor-specific photodynamic therapy
Conventional photodynamic therapy (PDT) is hindered by oxygen-dependent photosensitization pathways and high-power-density photoexcitation. Here, the authors develop polymer-based organic photosensitizers (PSs) through PS skeleton design and side-chain engineering to allow tumor-specific PDT under oxygen-free conditions using ultralow-power 808 nm photoexcitation.
- Yufu Tang
- , Yuanyuan Li
- & Bin Liu
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Article
| Open AccessMetabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas
Cancer associated fibroblasts can shape the tumor microenvironment (TME) and modulate immune infiltration. Here the authors characterize the TME in preclinical models of softtissue sarcomas, identifying a subset of “glycolytic” cancer-associated fibroblasts that inhibit cytotoxic T cell infiltration into the tumor parenchyma.
- Marina T. Broz
- , Emily Y. Ko
- & Jlenia Guarnerio
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Article
| Open AccessReciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer
TP63 is a master regulator transcription factor in squamous cell carcinomas (SCCs). Here the authors report that TP63 suppresses IFNγ signaling in SCC tumors and that its inhibition is associated with enhanced anti-tumor immunity and response to anti-PD1.
- Yuan Jiang
- , Yueyuan Zheng
- & Yan-Yi Jiang
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Article
| Open AccessCombined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer
The MAPK pathway is an important therapeutic target in pancreatic ductal adenocarcinoma (PDAC), but success is limited by pathway reactivation, which drives resistance. Here, the authors investigate the mechanism underlying HER2-reactivation post KRAS-MAPK inhibition, identifying combination of MAPK and HER2 inhibition as a therapeutic strategy.
- Ashenafi Bulle
- , Peng Liu
- & Kian-Huat Lim
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Article
| Open AccessAllele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells
Quantifying the impact of copy-number alterations (CNAs) on gene expression at the subclone level in cancer remains a challenge. Here, the authors develop TreeAlign, a method that integrates sample-matched single-cell DNA and RNA sequencing data to infer the impact of CNAs on subclonal gene expression.
- Hongyu Shi
- , Marc J. Williams
- & Sohrab P. Shah
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Article
| Open AccessThe bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease
Here, the authors develop a hybrid agent-based model to quantify the contributions of intrinsic cellular mechanisms and bone ecosystem factors to therapy resistance in multiple myeloma. They show that intrinsic mechanisms are essential for resistance, and that the bone microenvironment provides a protective niche that increases the likelihood.
- Ryan T. Bishop
- , Anna K. Miller
- & David Basanta
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Article
| Open AccessExemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial
Intrinsic and acquired resistances to CDK4/6 inhibitors have been described in patients with breast cancer. Here the authors report the results from a phase I/II clinical trial of the aromatase inhibitor exemestane plus everolimus (mTOR inhibitor) and palbociclib (CDK4/6i) in patients with metastatic breast cancer, assessing safety, clinical efficacy, as well as genomic and transcriptomic determinants of resistance.
- Jorge Gómez Tejeda Zañudo
- , Romualdo Barroso-Sousa
- & Nikhil Wagle
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Article
| Open AccessPolyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer
Ferroptosis plays an important role in response to radiotherapy and chemotherapy, however, the sensitivity of cancer cell to ferroptosis varies. Here, the authors show that ODC1-mediated polyamine synthesis induces ferroptosis and demonstrate the potential of targeting this axis by combining polyamine supplements with radiotherapy or chemotherapy in preclinical lung cancer models.
- Guoshu Bi
- , Jiaqi Liang
- & Cheng Zhan
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Article
| Open AccessNMR and MS reveal characteristic metabolome atlas and optimize esophageal squamous cell carcinoma early detection
Metabolic changes often occur during the early stages of cancer development. Here, the authors develop metabolomics signatures from tissues, pre- and post-operative sera and urines in esophageal squamous cell carcinoma, which may aid in early diagnosis.
- Yan Zhao
- , Changchun Ma
- & Yan Lin
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Article
| Open AccessOncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
Metastasis arises from disseminated tumour cells (DTCs) while the underlying mechanism of DTCs plasticity remains underexplored. Here, the authors show that spatially organized oncogenic enhancers on chromatin sustain the establishment of retinoic acid (RA)-stimulated transcriptional memory through activation of SOX9, supporting the escape of quiescent DTCs from NK-mediated immune surveillance.
- Daniela Michelatti
- , Sven Beyes
- & Alessio Zippo
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Article
| Open AccessDrug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Here, the authors show that EGFR lung cancer mutations promote the assembly of kinase-active dimers within ligand-free EGFR oligomers. These dimers bind ligand with high affinity and promote tumor growth.
- R. Sumanth Iyer
- , Sarah R. Needham
- & Marisa L. Martin-Fernandez
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Article
| Open AccessThe evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis
Detailed molecular studies are required to understand the differences between primary and metastatic upper tract urothelial carcinoma (UTUC). Here, the authors use genomics, transcriptomics and imaging mass cytometry to characterise the molecular profiles of primary and metastatic UTUC, and find that molecular subtypes remain highly conserved.
- Kentaro Ohara
- , André Figueiredo Rendeiro
- & Juan Miguel Mosquera
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Article
| Open AccessHematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes
Secondary resistance to venetoclax in patients with myelodysplastic syndromes (MDS) is not completely elucidated. Here, the authors show that haematopoietic stem cells with a granulo-monocytic differentiation transcriptional state drive secondary resistance to venetoclax in MDS patients who previously failed hypomethylating agent therapy.
- Juan Jose Rodriguez-Sevilla
- , Irene Ganan-Gomez
- & Simona Colla
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Article
| Open AccessSenescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment
Recent evidence suggests that senescence can negatively affect immune cell function. Here the authors show that accumulation of senescent cells in tumor-bearing mice previously exposed to irradiation or chemotherapy is associated with resistance to immune checkpoint inhibitors, associated with an exacerbated immunosuppressive profile of tumor-infiltrating myeloid cells.
- Damien Maggiorani
- , Oanh Le
- & Christian Beauséjour
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Article
| Open AccessMesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes
Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer. This study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their substrate selectivity.
- Ambrocio Sanchez
- , Pedro Ortega
- & Rémi Buisson
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Article
| Open AccessTherapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability
MYC oncogene promotes tumourigenesis by coordinating cancer cell proliferation with metabolic adaptation to the consequent excessive oxidative stress. Here, the authors show that nudix hydrolase 1 (NUDT1) is a MYC-driven metabolic vulnerability and generate a NUDT1 protein degrader to treat preclinical MYC-associated cancer.
- Minhui Ye
- , Yingzhe Fang
- & Guoliang Qing
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