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| Open AccessThe proteomic landscape of soft tissue sarcomas
Characterising the molecular profile of soft tissue sarcomas (STS) remains critical. Here, the authors analyse samples from 321 STS patients across 11 histological subtypes using proteomics and identify prognostic signatures that can be applied to multiple subtypes.
- Jessica Burns
- , Christopher P. Wilding
- & Paul H. Huang
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Article
| Open AccessThe transcriptional landscape and diagnostic potential of long non-coding RNAs in esophageal squamous cell carcinoma
Esophageal squamous cell carcinoma is difficult to detect at early stages, and late detection is often linked to poor prognosis. Here, the authors develop a lncRNA signature predictive of ESCC and validate across multiple external cohorts.
- Meng Zhou
- , Siqi Bao
- & Zhihua Liu
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Article
| Open AccessNFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation
Pancreatic acinar differentiation can be tumour suppressive for pancreatic ductal adenocarcinoma (PDAC). Here the authors identify nuclear factor I family of transcription factors NFIC as a regulator of pancreatic acinar cell function that restrains mutant KRas-driven pancreas cancer initiation in mice.
- Isidoro Cobo
- , Sumit Paliwal
- & Francisco X. Real
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Article
| Open AccessTargeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
Repair of topoisomerase 1 (TOP1) DNA protein crosslinks (DPC) limits the efficacy of the TOP1 inhibitor irinotecan in cancer therapy. Here, the authors identify pevonedistat, NEDD8 inhibitor, as synergistic with irinotecan by blocking neddylation-activated ubiquitin/proteasomal degradation of TOP1-DPC.
- Yilun Sun
- , Simone A. Baechler
- & Yves Pommier
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Article
| Open AccessOncogenic structural aberration landscape in gastric cancer genomes
Gastric cancers (GC) are driven by genomic alterations, but the underlying molecular mechanisms remain unclear. Here, the authors analyse the structural rearrangement landscape of 170 GCs using whole-genome sequencing, identify recurrent structural variant hotspots and find oncogene amplicons driven by extrachromosomal DNA.
- Mihoko Saito-Adachi
- , Natsuko Hama
- & Tatsuhiro Shibata
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Article
| Open AccessNivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial
A combination of chemoradiotherapy followed by brachytherapy is recommended for patients with locally-advanced cervical cancer (LACC), however there is still a high risk of disease recurrence. Here the authors report clinical outcomes and immunologic correlates of a clinical trial of the PD-1 inhibitor nivolumab in combination with chemoradiotherapy in LACC patients.
- Manuel Rodrigues
- , Giulia Vanoni
- & Emanuela Romano
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Article
| Open AccessHypoxia induced responses are reflected in the stromal proteome of breast cancer
The role of hypoxia and metabolic reprogramming in breast cancer remains to be explored. Here, the authors investigate the landscape of secreted proteins in response to hypoxia in breast cancer cell lines and identify a stromal-based hypoxia profile in breast cancer tissue.
- Silje Kjølle
- , Kenneth Finne
- & Lars A. Akslen
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Article
| Open AccessA platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma
GM-CSF-secreting whole-cell cancer vaccine (GVAX) promotes T-cell response against a range of tumor associated antigens in patients with pancreatic adenocarcinoma (PDA). Here the authors report the results of the initial three treatment arms of a platform trial of neoadjuvant and adjuvant GVAX alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable PDA.
- Thatcher Heumann
- , Carol Judkins
- & Lei Zheng
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Article
| Open AccessATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion
The ATR kinase has essential functions apart from its role in DNA replication stress. Here the authors find that in mouse primary B cells ATR tempers the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.
- Demis Menolfi
- , Brian J. Lee
- & Shan Zha
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Article
| Open AccessSingle cell profiling of female breast fibroadenoma reveals distinct epithelial cell compositions and therapeutic targets
Fibroadenoma occurrence is linked to increased long-term risk of breast carcinoma, however, the lack of models has made understanding this mechanism unclear. Here, the authors use single cell RNA-seq to identify dysregulation of epithelial cells and develop organoid models to study treatment resistance.
- Zhigang Chen
- , Yi Zhang
- & Jian Huang
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Article
| Open AccessPhase 1b trial of anti-EGFR antibody JMT101 and Osimertinib in EGFR exon 20 insertion-positive non-small-cell lung cancer
Patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions are resistant to early generation EGFR tyrosine kinase inhibitors (TKI). Here, the authors report the safety and preliminary efficacy of a phase I clinical trial JMT101, an anti-EGFR antibody, combined with EGFR-TKI, afatinib or osimertinib, in patients with NSCLC.
- Shen Zhao
- , Wu Zhuang
- & Wenfeng Fang
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Article
| Open AccessA pilot study of lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell therapy in patients with advanced solid tumors
The majority of adoptive T cell therapy-based clinical studies are based on the ex vivo expansion of neoantigen-specific tumor infiltrating lymphocytes. Here the authors report the results of a pilot study of adoptive cell therapy with personalized neoantigen-specific CD8 + T cells obtained from peripheral blood mononuclear cells in patients with locally advanced or metastatic solid tumors refractory.
- Dandan Li
- , Chao Chen
- & Rui-Hua Xu
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Article
| Open AccessNeutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies
B cell malignancies resistant to conventional treatments are potentially sensitive to CAR-T cell immune therapy, but its clinical applicability is limited by immune related adverse effects. Here authors show in a humanized mouse model that blocking IFNγ with the monoclonal antibody emapalumab mitigates the adverse effects of CAR.CD19-T cells without compromising their anti-lymphoma efficacy.
- Simona Manni
- , Francesca Del Bufalo
- & Concetta Quintarelli
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Article
| Open AccessALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
Chimeric antigen receptor T (CAR-T) cells represent a breakthrough in the treatment of haematopoietic malignancies, however, in solid tumours this form of immune therapy is hampered by the scarcity of suitable targets showing high level tumour-restricted expression. Here authors generate CAR-T cells that target an osteosarcoma-specific isoform of alkaline phosphatase and show efficacy in orthotopic animal models while sparing healthy tissues.
- Nadia Mensali
- , Hakan Köksal
- & Sébastien Wälchli
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Article
| Open AccessIdentification of BRCA1/2 mutation female carriers using circulating microRNA profiles
BRCA1/2 mutations are known to increase risk of breast and ovarian cancer but carrier status in healthy individuals is unknown without genetic testing. Here, the authors created a circulating miRNA signature to predict BRCA1/2 carrier status in healthy individuals to aid the decision process on genetic testing.
- Kevin Elias
- , Urszula Smyczynska
- & Dipanjan Chowdhury
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Article
| Open AccessA high-throughput test enables specific detection of hepatocellular carcinoma
DNA methylation analysis is a promising method to detect liver cancer. Here, the authors develop a 5 CpG site signature which can detect HCC at high specificity across multiple cohorts.
- David Cheishvili
- , Chifat Wong
- & Mamun Al Mahtab
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Article
| Open AccessDrug screening at single-organoid resolution via bioprinting and interferometry
Traditional 2D cell culture platforms do not accurately reflect the physiology of human tumors. Here, authors combine bioprinting and high-speed live cell interferometry with machine learning to measure drug sensitivity at single-organoid resolution in a label-free manner.
- Peyton J. Tebon
- , Bowen Wang
- & Alice Soragni
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Article
| Open AccessLysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity
Lysophosphatidic acid is known to increase in concentration in multiple cancer types. Here, the authors show it affects CD8 T cell metabolism, phenotype, and effector functions, and plasma concentrations appear predictive of response to immunotherapy.
- Jacqueline A. Turner
- , Malia A. Fredrickson
- & Raul M. Torres
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Article
| Open AccessNOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1
Patients with lung adenocarcinoma (LUAD) patients carrying EGFR mutations are often treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), but sensitivity to the therapy varies. Here, using 3D printed patient derived xenograft models, the authors identify a NOTCH mutation as an indicator of favourable response to EGFR-TKI in LUAD.
- Bin Zhang
- , Shaowei Dong
- & Chang Zou
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Article
| Open AccessThe blood proteome of imminent lung cancer diagnosis
Lung cancer screening could enhance early diagnosis and treatment. Here, the authors used proteomic analysis of pre-diagnosis samples across 6 cohorts to identify 36 proteins associated with imminent lung cancer diagnosis.
- Demetrius Albanes
- , Karine Alcala
- & Wei Zheng
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Article
| Open AccessLeukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation
Graft-versus-leukemia reactions are required for the eradication of myeloid malignancies after allogeneic hematopoietic cell transplantation. However, treatment efficacy is variable, depending on the immunological response. Here the authors show that dysfunction of HLA heterogeneity is associated with post-transplant leukemia relapse.
- Simona Pagliuca
- , Carmelo Gurnari
- & Jaroslaw P. Maciejewski
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Article
| Open AccessIdentification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer
Long-term metastatic relapse is observed in patients with luminal breast cancer (BC). Here, the authors show that fatty acid amide hydrolase is a tumour suppressor for lung metastasis in mouse models of BC and a predictor of metastasis in patients with luminal BC.
- Isabel Tundidor
- , Marta Seijo-Vila
- & Eduardo Pérez-Gómez
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Article
| Open AccessLysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase
Novel strategies are needed to overcome chemotherapy resistance. Here the authors report chemotherapy induces the phosphorylation of Lysyl oxidase-like 3, which in turn stabilizes dihydroorotate dehydrogenase (DHODH) and that DHODH inhibitor sensitizes tumor cells to oxaliplatin treatment by inducing ferroptosis in liver cancer.
- Meixiao Zhan
- , Yufeng Ding
- & Xiongjun Wang
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| Open AccessTowards evidence-based response criteria for cancer immunotherapy
Early detection of immunotherapy-induced tumor response is of major benefit for patients but can be complicated by therapy-induced pseudoprogression. A consensus guideline-iRECIST- was developed as a modification of Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). Here we describe which next steps are required to test its validity and how novel approaches for response criteria might be developed and included.
- Elena Garralda
- , Scott A. Laurie
- & Elisabeth G. E. de Vries
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Article
| Open AccessSingle-cell analysis of gastric signet ring cell carcinoma reveals cytological and immune microenvironment features
The tumour microenvironment in signet ring cell carcinoma (SRCC) remains to be characterised. Here, the authors perform single-cell RNA sequencing and reveal distinct features compared to moderately/poorly differentiated adenocarcinoma.
- Weizhu Zhao
- , Yanfei Jia
- & Jie Chai
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Article
| Open AccessDurvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin
Single immune checkpoint blockade has shown limited activity in patients with neuroendocrine neoplasms (NENs). Here the authors report the results of a phase II clinical trial of durvalumab (anti-PD-L1) and tremelimumab (anti CTLA-4) in patients with advanced NENs of gastroenteropancreatic and lung origin.
- J. Capdevila
- , J. Hernando
- & J. L. Manzano
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Article
| Open AccessMicrobial synthesis of Prussian blue for potentiating checkpoint blockade immunotherapy
Prussian blue has been used as a photothermal agent for cancer therapy. Here the authors describe the production of Prussian blue nanoparticles from S. oneidensis MR-1 bacteria and show that a Prussian blue-based mitochondria-targeting nanoplatform potentiates response to immune checkpoint blockade.
- Dongdong Wang
- , Jiawei Liu
- & Yanli Zhao
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Article
| Open AccessDasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia
Despite playing a central role the treatment of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), resistance to glucocorticoids remains a major obstacle. Here, the authors identify activation of PI3K/mTOR and CREB pathways as a driver of GC-resistance in BCP-ALL and restore sensitivity using the multi kinase inhibitor, dasatinib.
- Jolanda Sarno
- , Pablo Domizi
- & Kara L. Davis
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Article
| Open AccessAlanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss
Cancers with concomitant SMARCA4/2 deficiencies are often resistant to chemotherapies and confer a poor prognosis. Here, the authors identify a metabolic dependency of these tumours on glutamine as an energy source and, using multiple approaches, demonstrate the efficacy of therapeutically targeting this vulnerability.
- Xianbing Zhu
- , Zheng Fu
- & Sidong Huang
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Article
| Open AccessADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer
Resistance to 5-fluorouracil and cisplatin (5FU + CDDP) presents a major issue in patients with gastric cancer. Here, the authors establish 5FU + CDDP resistant intestinal gastric cancer patient-derived organoids and identify JAK/STAT-ADAR1 altered lipid metabolism as a regulator of chemoresistance.
- Tin-Lok Wong
- , Jia-Jian Loh
- & Stephanie Ma
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Article
| Open AccessERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
Ubiquitination and deubiquitination processes regulate the stability of PD-1, affecting T cell biology. Here the authors identify the ubiquitin-specific protease 5 (USP5) as a deubiquitinase for PD-1 and show that USP5 inhibition in combination with a MEK inhibitor or anti-CTLA-4 could promote anti-tumor immune responses in preclinical models.
- Xiangling Xiao
- , Jie Shi
- & Jinfang Zhang
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Article
| Open AccessClinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma
Dual PD-1 and CTLA-4 checkpoint blockade has proven effective in several cancer types. Here the authors report the results of a clinical trial of anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) in patients with recurrent/metastatic EBV-positive nasopharyngeal carcinoma.
- Darren Wan-Teck Lim
- , Hsiang-Fong Kao
- & N. Gopalakrishna Iyer
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Article
| Open Accessp140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response
The p140Cap adaptor protein is a tumour suppressor associated with improved prognosis in breast cancer. Here, the authors identify a role for p140Cap in preventing the immunosuppressive and pro-tumour function of polymorphonuclear myeloid-derived suppressor cells via downmodulation of the β-Catenin/Tumor Initiating Cells/G-CSF axi
- Vincenzo Salemme
- , Mauro Vedelago
- & Paola Defilippi
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| Open AccessPhase II trial of neoadjuvant sitravatinib plus nivolumab in patients undergoing nephrectomy for locally advanced clear cell renal cell carcinoma
In patients with locally advanced clear cell renal cell carcinoma (ccRCC), neoadjuvant therapy prior to curative nephrectomy has been shown to improve patient outcomes. Here, the authors report the safety and radiological efficacy of a phase II clinical trial investigating neoadjuvant sitravatinib (tyrosine kinase inhibitor) and nivolumab (PD-1 inhibitor) in locally advanced ccRCC.
- Jose A. Karam
- , Pavlos Msaouel
- & Christopher G. Wood
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Article
| Open AccessSkin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche
Tumor microenvironment elements can influence tumor state, including in skin basal cell carcinomas. Here the authors show that spatially organized and self-propagating TREM2+ tumor associated macrophages promote Ly6D- tumor cell proliferation via secretion of oncostatin M.
- Daniel Haensel
- , Bence Daniel
- & Anthony E. Oro
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Article
| Open AccessHepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis
Activated hepatic stellate cells (aHSC) promote hepatocellular carcinoma (HCC). Here the authors show that selective ablation of stearoyl CoA desaturase-2 in aHSC suppresses leukotriene B4 receptor 2-dependent nuclear β-catenin signaling, preventing liver tumorigenesis.
- Sonal Sinha
- , Satoka Aizawa
- & Hidekazu Tsukamoto
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Article
| Open AccessIntegrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence
Genomic landscape studies of malignant germ cell tumors (GCTs) that occur in children, adolescents and young adults are limited. Here the authors perform multi-omics profiling of different types of GCTs across the age spectrum from 0–24 years and show that WNT signalling pathway is activated in GCTs and is associated with poor clinical outcomes.
- Lin Xu
- , Joshua L. Pierce
- & James F. Amatruda
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Article
| Open AccessType I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment
Astrocytes can influence several steps of the metastatic process in the brain. Here the authors show that type I interferon response in astrocytes facilitates brain metastasis by increasing recruitment of tumor promoting monocytic myeloid cells.
- Weili Ma
- , Maria Cecília Oliveira-Nunes
- & Qing Chen
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Article
| Open AccessKK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer
The presence of breast cancer stem cells is associated with therapy resistance in patients with triple-negative breast cancer (TNBC). Here, the authors identify KK-LC-1-mediated YAP signaling as a driver of TNBC stemness and develop a therapeutic molecule to target this axis in preclinical models of TNBC.
- Jiawen Bu
- , Yixiao Zhang
- & Caigang Liu
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Article
| Open AccessGenomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients
Xeroderma pigmentosum (XP) is a rare genetic disorder that is associated with a higher risk of skin cancer. Here, the authors analyse the genomes of skin cancers from patients across five different XP groups, revealing genetic and molecular factors related to the mutational profile and UV-related mutagenesis in XP.
- Andrey A. Yurchenko
- , Fatemeh Rajabi
- & Sergey I. Nikolaev
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Article
| Open AccessMetabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma
The molecular mechanisms underlying MYC overexpression in group 3 medulloblastoma remain to be explored. Here, the authors highlight the involvement of the mitochondrial pyruvate carrier- SOD2 signalling pathway in the regulation of MYC protein abundance.
- Emma Martell
- , Helgi Kuzmychova
- & Tanveer Sharif
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Article
| Open AccessDNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC
DNA polymerase 1 (POLD1) has an important role in DNA damage repair and is frequently upregulated in cancer. Here, the authors report a non-canonical role of POLD1 wherein it stabilises MYC protein, creating a positive feedback loop with POLD1 expression and driving bladder cancer progression and metastasis.
- Yejinpeng Wang
- , Lingao Ju
- & Xinghuan Wang
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Article
| Open AccessAnti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4
IgE antibodies targeting cancer antigens can be used for immunotherapy. Here the authors present an IgE antibody targeting the melanoma-associated antigen, chondroitin sulphate proteoglycan 4, that recognises human melanoma, stimulates tumour cell cytotoxicity, and restricts tumour growth in humanised mouse models.
- Jitesh Chauhan
- , Melanie Grandits
- & Heather J. Bax
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Article
| Open AccessImmune cellular patterns of distribution affect outcomes of patients with non-small cell lung cancer
The spatial distribution of cellular compartments within the tumour microenvironment in non-small cell lung cancer (NSCLC) remains to be investigated. Here, the authors identify distinct cell populations of tumour cells and tumour-associated immune cell phenotypes with different spatial distributions in NSCLC.
- Edwin Roger Parra
- , Jiexin Zhang
- & Ignacio Ivan Wistuba
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Article
| Open AccessMetabolomic differentiation of benign vs malignant pulmonary nodules with high specificity via high-resolution mass spectrometry analysis of patient sera
Detection of lung adenocarcinoma through serum sampling could be an alternative to CT scanning. Here, the authors use global metabolomics to create a 27 metabolite signature, which showed accuracy in detection in an external validation cohort.
- Yao Yao
- , Xueping Wang
- & Yumin Hu
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Article
| Open AccessHAPLN1 potentiates peritoneal metastasis in pancreatic cancer
The presence of peritoneal metastasis in pancreatic cancers is associated with poor prognosis. Here the authors show that hyaluronan and proteoglycan link protein-1 (HAPLN1) promotes tumour cell plasticity and pro-tumoral immune microenvironment to facilitate peritoneal dissemination in pancreatic cancers.
- Lena Wiedmann
- , Francesca De Angelis Rigotti
- & Juan Rodriguez-Vita
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Article
| Open AccessIn silico cancer immunotherapy trials uncover the consequences of therapy-specific response patterns for clinical trial design and outcome
Conventional clinical trial design methods are not necessarily tailored for the unique characteristics of immunotherapies. Here the authors use late-stage in silico cancer immunotherapy trials to investigate how design decisions affect the trial outcome.
- Jeroen H. A. Creemers
- , Ankur Ankan
- & Johannes Textor
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Article
| Open Access3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma
Ependymoma is a tumor of the brain or spinal cord with the two most common and aggressive types mainly occurring in children. Here the authors employ 3D genomics and epigenomics to reveal targets for aggressive ependymoma tumors in children.
- Konstantin Okonechnikov
- , Aylin Camgöz
- & Lukas Chavez
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Article
| Open AccessSema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma
Wnt signaling is dysregulated in glioblastoma (GBM). Here the authors show that Semaphorin 3C drives Wnt signaling through Rac1-dependent β-catenin nuclear accumulation and that dual blockade of Semaphorin 3C and Wnt pathway reduces the growth of GBM in vivo.
- Jing Hao
- , Xiangzi Han
- & Jennifer S. Yu