Featured
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Article
| Open AccessBreast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis
Breast cancer metastasis to the brain is rising in prevalence and is an increasingly lethal threat to the patients. Here, the authors show miR-199b-5p, secreted by some breast cancer cells and detected at a higher level in patients with brain metastases, impairs the metabolic coupling between neurons and astrocytes to facilitate development of brain metastasis.
- Xianhui Ruan
- , Wei Yan
- & Shizhen Emily Wang
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Article
| Open AccessL-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial
Recent studies show that targeting CXCL12 can improve the effect of radiotherapy (RT) in preclinical models of glioblastoma (GBM). Here, the authors report the safety and preliminary efficacy of a phase I/II clinical trial investigating an L-RNA aptamer-based CXCL12 inhibitor (NOX-A12) in combination with RT in patients with newly-diagnosed GBM.
- Frank A. Giordano
- , Julian P. Layer
- & Michael Hölzel
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Article
| Open AccessC5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
PARP inhibitors (PARPi) have been approved for the treatment of metastatic triple-negative breast cancer (BC), however resistance and recurrence are often observed. Here, in preclinical models of BRCA1/2 wild type and homologous recombination competent BC, the authors show that C5aR1-positive tumor associated macrophages are associated with PARPi-resistance, suggesting targeting C5aR1 as a therapeutic option.
- Xi Li
- , Alfonso Poire
- & Gordon B. Mills
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Article
| Open AccessGlioblastoma disrupts cortical network activity at multiple spatial and temporal scales
The precise onset, temporal progression and spatial extent of neuron-tumor crosstalk in brain with Glioblastoma (GBM) are not fully understood. Here authors, using a genetic GBM mouse model, show widespread glutamate accumulation, chronic neural activity disruption between cells and brain areas, depending on tumor expansion rate and genotype with altered tumor and neural activity dynamics when adding glypican6.
- Jochen Meyer
- , Kwanha Yu
- & Jeffrey Noebels
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Article
| Open AccessProteomic analysis of the urothelial cancer landscape
Urothelial cancer is a challenging disease and an emerging field for targeted therapies. Here, the authors optimize clinical proteomics to provide proteome-level data on tumor specificity and identify robust prognostic subtypes with predictive information for repurposed drug candidates.
- Franz F. Dressler
- , Falk Diedrichs
- & Ákos Végvári
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Article
| Open AccessDeleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies
Treatment failure following chimaeric antigen receptor (CAR) T cell therapy is common yet incompletely understood. In this study, the authors demonstrate that deletion of the mitochondrial negative regulator, MCJ, in CAR T cells promotes target cell killing ex vivo and augments their efficacy in an in vivo B cell leukaemia model.
- Meng-Han Wu
- , Felipe Valenca-Pereira
- & Mercedes Rincon
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Article
| Open AccessImmune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer
In the phase 2 study LCCC1520 (NCT02690558), clinical activity of pembrolizumab in combination with gemcitabine and cisplatin as neoadjuvant therapy in patients with muscle-invasive bladder cancer has been reported. Here the authors present molecular and immune cellular features associated with response to neoadjuvant chemo-immunotherapy.
- Wolfgang Beckabir
- , Mi Zhou
- & Benjamin G. Vincent
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Article
| Open AccessHDAC activity is dispensable for repression of cell-cycle genes by DREAM and E2F:RB complexes
Here, the authors investigate the interplay among DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression, suggesting that E2F:RB and DREAM complexes can repress cell-cycle genes without relying on HDAC activity.
- Alison K. Barrett
- , Manisha R. Shingare
- & Gerd A. Müller
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Article
| Open AccessH2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours
Histone H2AX has a known role in DNA damage repair but interestingly, its loss is associated with resistance to poly(ADP-ribose) polymerase (PARP) inhibition in BRCA-deficient tumours. Here, the authors identify a role of γH2AX in the degradation of replication forks and demonstrate that H2AX loss drives PARP inhibitor resistance via increased stressed fork stability in BRCA-deficient tumours.
- Diego Dibitetto
- , Martin Liptay
- & Sven Rottenberg
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Article
| Open AccessSingle-cell and spatial transcriptomics analysis of non-small cell lung cancer
Myeloid cell populations play a critical role in lung cancer progression. Here, the authors use scRNA-seq and spatial transcriptomics to identify changes in the phenotype of macrophages within the tumour microenvironment.
- Marco De Zuani
- , Haoliang Xue
- & Ana Cvejic
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Article
| Open AccessDrug screening on digital microfluidics for cancer precision medicine
In-vitro platforms for personalized cancer diagnosis is required high sensitivity. Here, the authors developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine.
- Jiao Zhai
- , Yingying Liu
- & Yanwei Jia
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Article
| Open AccessIntegrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis
While it is known that localised prostate cancer is characterised by clonal heterogeneity, the clonal origin of synchronous lymph node (LN) metastases remains poorly understood. Here, the authors analyse the clonal origin of LN metastases in prostate cancer patients using multi-region sequencing.
- Udit Singhal
- , Srinivas Nallandhighal
- & Simpa S. Salami
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Article
| Open AccessMultiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer
Intratumoral heterogeneity has been documented in multiple cancer types, and can be linked to treatment resistance. Here, the authors analyse multiregional samples from colorectal cancers and show gene expression subtypes which are less vulnerable to heterogeneity and may partly contribute to differential patient survival.
- Jonas Langerud
- , Ina A. Eilertsen
- & Anita Sveen
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Article
| Open AccessDeterminants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci
The role of non-coding mutations in cancer progression and immune evasion needs to be further explored. Here, the authors investigate the potential of common somatic and germline 3′ untranslated region variants in predicting response to immunotherapy in gastric patients.
- Christos Miliotis
- , Yuling Ma
- & Ioannis S. Vlachos
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Article
| Open AccessPriming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells
Phenotypic changes in exhausted T cells are linked to chromatin remodeling. Here the authors show that pharmacological inhibition of the H3K4me1/2 demethylase LSD1 promotes the persistence and enhances the therapeutic activity of adoptively transferred T cells for cancer therapy.
- Fengqi Qiu
- , Peishan Jiang
- & Wanqiang Sheng
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Article
| Open AccessCell of origin epigenetic priming determines susceptibility to Tet2 mutation
HSC mutations lead to diverse clonal hematopoiesis outcomes. This study shows how epigenetic traits can predispose clones for dominance. Sox4 increases sensitivity to Tet2 KO, offering insights into variable phenotypes despite identical mutations.
- Giulia Schiroli
- , Vinay Kartha
- & David T. Scadden
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Article
| Open AccessProdrug-conjugated tumor-seeking commensals for targeted cancer therapy
The chemotherapeutic efficacy of prodrug is limited by its cancer-targeting ability. Here this group reports an engineered commensal Lactobacillus plantarum strain with anticancer prodrugs loading on the surface for nasopharyngeal carcinoma cell-targeting and growth inhibition.
- Haosheng Shen
- , Changyu Zhang
- & Matthew Wook Chang
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Article
| Open AccessTargeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer
The ability of anti-cancer therapies such as radiotherapy, chemotherapy and immunotherapy to induce ferroptosis has been linked to their efficacy. Here, the authors demonstrate that SOX13 promotes ferroptosis-resistance via transactivation of SCAF1, identifying SOX13 as a targeted therapeutic vulnerability in gastric cancer.
- Hui Yang
- , Qingqing Li
- & Mingzhe Ma
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Article
| Open AccessTryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis
Amino acids availability is normally a limitation for protein synthesis and can determine cancer progression and therapy response. Here, the authors show that MYC-associated cancer has a dependency on tryptophan not because of translation regulation, but Indole 3-Pyruvate synthesis.
- Niranjan Venkateswaran
- , Roy Garcia
- & Maralice Conacci-Sorrell
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Article
| Open AccessHistopathologic image–based deep learning classifier for predicting platinum-based treatment responses in high-grade serous ovarian cancer
Predicting the response to platinum-based chemotherapy in high-grade serous ovarian carcinoma (HGSOC) remains challenging. Here, the authors develop the histopathology image-based Pathologic Risk Classifier for HGSOC - PathoRiCH - to predict and stratify HGSOC patient response to therapy, especially when combined with molecular biomarkers.
- Byungsoo Ahn
- , Damin Moon
- & Eunhyang Park
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Article
| Open AccessHsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation
Hsc70 (heat shock protein family A member 8) is a cytoplasmic chaperone protein involved in endosomal micro-autophagy and chaperone-mediated autophagy. Here the authors report that Hsc70 promotes lysosomal degradation of PD-L1 and that its overexpression promotes anti-tumor immune responses in preclinical cancer models.
- Xiaoyan Xu
- , Tingxue Xie
- & Hongguang Xia
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Article
| Open AccessStimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse
Despite initial treatment with surgical resection, glioblastoma multiforme (GBM) frequently recurs. Here the authors report the design of an immunostimulatory autolysing Salmonella based-nanocapsule delivery system, promoting anti-tumor immune responses and preventing postoperative relapse in preclinical GBM models.
- Yulin Zhang
- , Kaiyan Xi
- & Shilei Ni
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Article
| Open AccessMitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC
The relevance of mitochondrial cysteine metabolism to ferroptosis is unknown. Here, Ward et al. show that mitochondrial Fe-S cluster synthesis persists under cysteine limitation via the catabolism of glutathione and at the expense of cell viability.
- Nathan P. Ward
- , Sang Jun Yoon
- & Gina M. DeNicola
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Article
| Open AccessFerritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
The mechanisms leading to acquired resistance to targeted therapy in cancer are not completely understood. Here, the authors show that ferritinophagy mediates adaptive resistance to Osimertinib, and that combining this EGFR tyrosine kinase inhibitor with copper ionophores improves its therapeutic efficacy in preclinical models of non-small cell lung cancer.
- Hui Wang
- , Qianfan Hu
- & Feng Jiang
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Article
| Open AccessAn improved epigenetic counter to track mitotic age in normal and precancerous tissues
DNA methylation (DNAm) clocks can track mitotic age, but their potential use for cancer risk prediction remains less explored. Here, the authors develop a DNAm counter of total mitotic age (stemTOC) that shows an increase of mitotic age in normal tissues and precancerous lesions.
- Tianyu Zhu
- , Huige Tong
- & Andrew E. Teschendorff
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Article
| Open AccessLong-term relapse-free survival enabled by integrating targeted antibacteria in antitumor treatment
Tumor-resident intracellular microbiota (TRIM) could be a potential target for anticancer treatment. Here the authors report Au@Ag2Se nano-assemblies enabling bacterial killing, tumor inhibition and immune regulation in tumor microenvironment.
- Yuanlin Wang
- , Yaqian Han
- & Miao Yu
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Article
| Open Access1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma
Translocations and copy number variations that affect multiple myeloma (MM) have not been investigated at the single cell level. Here, single cell multi-omics reveal the relationship between epigenetic regulation and cytogenetic events that lead to the increase of cell proliferation in MM.
- Travis S. Johnson
- , Parvathi Sudha
- & Brian A. Walker
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Article
| Open AccessBone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes
Bone marrow stromal cells (BMSCs) are known to promote the development of drug resistance. Here, the authors investigate the chromatin remodeling and associated changes in gene expression in the multiple myeloma (MM) cells following their interactions with BMSCs, which are also observed in extramedullary disease (EMD).
- Moritz Binder
- , Raphael E. Szalat
- & Nikhil C. Munshi
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Article
| Open AccessWhole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers
Efforts to allow routine whole genome and transcriptome analysis (WGTA) for pediatric cancers in the clinic remain critical. Here, the authors present results of a unified genomics and bioinformatics pipeline for WGTA in paediatric cancers, the Personalized OncoGenomics (POG) program, with a focus on potential therapeutic targets.
- Rebecca J. Deyell
- , Yaoqing Shen
- & Shahrad R. Rassekh
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Article
| Open AccessCEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials
Cibisatamab is a T-cell bispecific antibody targeting the carcinoembryonic antigen (CEA) on tumor cells and CD3 epsilon chain on T cells. Here the authors report the results of two clinical trials of cibisatamab as monotherapy (NCT02324257) and in combination with atezolizumab (anti-PD-L1; NCT02650713) in patients with CEA-positive solid tumors.
- Neil H. Segal
- , Ignacio Melero
- & Guillem Argilés
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Article
| Open AccessProteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis
MAPK-driven tumorigenesis is often related to epithelial dedifferentiation but the regulatory mechanism is less clear. Here, the authors show that MAPK activation upregulates USP15 to promote deubiquitylation and stability of TBX3, a transcription factor implicated in thyroid development and differentiation, driving tumorigenesis in a BRAFV600E thyroid tumor model.
- Zhenlei Zhang
- , Yufan Wu
- & Li Zhao
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Article
| Open AccessOctyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways
The use of oncolytic viruses as a therapy for cancer is limited by mechanisms inhibiting viral replication in the tumor. Here, the authors show that a chemical derivative of itaconate, 4-octyl itaconate, increases oncolytic virus VSVΔ51 efficacy in various cancer models, through decreasing antiviral immunity.
- Naziia Kurmasheva
- , Aida Said
- & David Olagnier
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Article
| Open AccessJag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool
Dysregulation of basal progenitor cells induces esophageal tumorigenesis but the underlying mechanism is less explored. Here, the authors show that Jag1/2 deficiency promotes expansion of basal progenitor cells, leading to reduced squamous epithelial differentiation and enhanced formation of squamous cell carcinoma in the foregut.
- Haidi Huang
- , Yu Jiang
- & Yongchun Zhang
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Article
| Open AccessMAPP unravels frequent co-regulation of splicing and polyadenylation by RNA-binding proteins and their dysregulation in cancer
Here the authors apply the Motif Activity on Pre-mRNA Processing (MAPP) tool to standard RNA sequencing data, thereby unravelling the co-regulation of splicing and polyadenylation by RNA-binding proteins and their dysregulation in cancer.
- Maciej Bak
- , Erik van Nimwegen
- & Andreas J. Gruber
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Article
| Open AccessDisentangling oncogenic amplicons in esophageal adenocarcinoma
Esophageal adenocarcinoma is characterised by frequent amplifications in oncogenes. Here, the authors use short- and long-read sequencing approaches to analyze primary tumor samples and tumour-derived organoids and to investigate the mechanisms underlying complex amplifications.
- Alvin Wei Tian Ng
- , Dylan Peter McClurg
- & Rebecca C. Fitzgerald
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Article
| Open AccessSystematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types
Single-cell sequencing has enabled detailed analyses of the tumour microenvironment (TME). Here, the authors perform an integrative analysis of the TME using single-cell and spatial transcriptomics data from over a thousand tumours across thirty cancer types, identifying interferon-enriched community states predictive of immunotherapeutic responses.
- Junho Kang
- , Jun Hyeong Lee
- & Jong-Eun Park
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Article
| Open AccessDysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation
The impact of obesity on cancer remains insufficiently explored. Here the authors show that in mouse models, dysfunctional adipocytes exhibit low levels of BECN1 which induce YAP/TAZ activity to promote breast and colorectal tumor progression.
- Yaechan Song
- , Heeju Na
- & Han-Woong Lee
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Article
| Open AccessdsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe
Anaplastic thyroid cancer (ATC) is a particularly aggressive cancer type with limited effective therapeutic options. Here, the authors identify the SUMO E3 ligase PIAS2 as a potential therapeutic target in ATC and mechanistically investigate its role in mitotic spindle and centrosome assembly.
- Joana S. Rodrigues
- , Miguel Chenlo
- & Clara V. Alvarez
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Article
| Open AccessmTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism
How cells adapt to glucose starvation is still elusive. Here, Levy et al. show that the mTOR substrate 4EBP1 protects human, mouse, and yeast cells from glucose starvation and is exploited by cancer cells to promote tumorigenesis.
- Tal Levy
- , Kai Voeltzke
- & Gabriel Leprivier
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Article
| Open AccessMammographic density mediates the protective effect of early-life body size on breast cancer risk
Mammographic density is known to be linked to breast cancer risk. Here, the authors use Mendelian randomization to estimate the effects of childhood body size and age at menarche on density phenotypes and breast cancer risk.
- Marina Vabistsevits
- , George Davey Smith
- & Eleanor Sanderson
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Article
| Open AccessPlatelets favor the outgrowth of established metastases
It is unclear if platelets regulate the growth of established metastases. Using syngeneic mouse models of metastasis, the authors show that platelets support the outgrowth of established metastases via immune suppression, and that targeting the platelet-specific receptor GPVI, efficiently reduces established metastases, providing a promising therapeutic avenue for inhibiting cancer metastasis.
- Maria J. Garcia-Leon
- , Cristina Liboni
- & Jacky G. Goetz
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Article
| Open AccessMethylation of ESCRT-III components regulates the timing of cytokinetic abscission
Methylation of CHMP2B regulates abscission timing by modulating ESCRT-III dynamics during cytokinesis. This methylation also plays a role in HIV-1 budding, highlighting the broader significance of ESCRT-III methylation.
- Aurélie Richard
- , Jérémy Berthelet
- & Souhila Medjkane
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Article
| Open AccessVOLTA: an enVironment-aware cOntrastive ceLl represenTation leArning for histopathology
While machine learning platforms can improve the assessment of Hematoxylin & Eosin (H&E) stained-tumour tissue images, current models typically require manual cell-type annotations in training. Here, the authors develop VOLTA, a self-supervised machine learning framework to improve cell representation learning in H&E images based on the cells environment
- Ramin Nakhli
- , Katherine Rich
- & Ali Bashashati
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Article
| Open AccessPretreatment with IL-15 and IL-18 rescues natural killer cells from granzyme B-mediated apoptosis after cryopreservation
Natural killer (NK) cells are assessed for various therapies, but sub-optimal cryopreservation dampens their clinical feasibility. Here the authors show that pretreating human NK cells with IL-15/IL-18 prior to cryopreservation improves NK cell post-thaw viability and functions, potentially via anti-apoptosis gene induction and granzyme B degranulation.
- Abdulla Berjis
- , Deeksha Muthumani
- & Neil C. Sheppard
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Article
| Open AccessThe STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion
It has been previously suggested that STING agonists can improve response to CAR-T therapy. Here the authors report the characterization of the STING agonist IMSA101, showing that STING-induced IL18 secretion enhances CAR-T activity in preclinical cancer models.
- Ugur Uslu
- , Lijun Sun
- & Carl H. June
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Article
| Open AccessPervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs
By applying Hi-C to cells derived from the tumors of 24 GBM patients, the authors show pervasive structural variation in GBM chromosomal organization. How such patient-to-patient variation explains the characteristic gene expression patterns in each tumor is investigated.
- Ting Xie
- , Adi Danieli-Mackay
- & Argyris Papantonis
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Article
| Open AccessChiral coordination polymer nanowires boost radiation-induced in situ tumor vaccination
Radiation-induced tumor vaccination is insufficient to elicit robust antitumor immune response. Here they combine chiral vidarabine monophosphate-gadolinium nanowires with immune checkpoint blockade therapy to synergistically induce antitumor immunity.
Reviewer recognition:
- Zhusheng Huang
- , Rong Gu
- & Ahu Yuan
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Article
| Open AccessNetwork-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis
Aberrant signalling pathway activity is relevant for tumour growth and resistance to therapy, but remains hard to understand and target. Here, the authors develop VESPA, a phosphoproteomics-based machine learning algorithm that can elucidate response and adaptation to drug perturbations in cancer signalling pathways.
- George Rosenberger
- , Wenxue Li
- & Andrea Califano
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Article
| Open AccessPD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression
Immune checkpoint inhibition is a successful form of immune therapy; however response rates vary widely among individual patients. Here authors show that circulating small extracellular vesicles might contribute to poor response to anti-PD-1 treatment by carrying PD-1 and CD80 which results in higher level of vesicular PD-L1 expression in the circulation at the expense of expression on tumour cell membranes, causing immunosuppression.
- Lin-Zhou Zhang
- , Jie-Gang Yang
- & Gang Chen
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