Featured
-
-
Article
| Open AccessBiology-guided deep learning predicts prognosis and cancer immunotherapy response
The clinical application of data-driven deep learning models remains challenging. Here, a biology-guided deep learning approach allows the simultaneous prediction of the tumour immune and stromal microenvironment status as well as treatment outcomes from medical images in gastric cancer.
- Yuming Jiang
- , Zhicheng Zhang
- & Ruijiang Li
-
Article
| Open AccessAndrogen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects
The prediction of mortality due to prostate cancer remains challenging. Here, the authors perform trans-ancestry metaanalysis with a focus on binding sites of the androgen receptor and develop a polygenic risk score.
- Shuji Ito
- , Xiaoxi Liu
- & Chikashi Terao
-
Article
| Open AccessSingle cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis
The metastatic tumour microenvironment in pancreatic ductal adenocarcinoma (PDAC) remains to be explored. Here, the authors perform single cell RNA sequencing analysis for synchronously resected PDAC primary tumours and matched liver metastases and find differences in cellular composition.
- Shu Zhang
- , Wen Fang
- & Ying Lv
-
Article
| Open AccessMolecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer
HER2-low breast cancer has recently been defined as a potential subtype for sensitivity to novel antibody-drug conjugates. Here, the authors analyse a multiomics cohort of 434 HER2-low patients and find an altered molecular status compared to other subtypes and the interpatient heterogeneity within this subtype.
- Lei-Jie Dai
- , Ding Ma
- & Zhi-Ming Shao
-
Article
| Open AccessDesmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors
Tumor stroma is a key component of the immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Here, in preclinical PDAC models, the authors show that depletion of FAP-expressing cancer associated fibroblasts with FAP-targeted CAR T cells results in a loss of the integrity of the desmoplastic matrix, rendering tumors more susceptible to sequential treatment with mesothelin-targeted CAR-T cells.
- Zebin Xiao
- , Leslie Todd
- & Ellen Puré
-
Article
| Open AccessEpigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics
The role of histone deacetylases (HDACs) in glioblastoma brain tumour stem cells (BTSCs) remains to be explored. Here, pharmacological inhibition and genetic loss of function approaches show that HDAC2 leads to the maintenance of BTSC growth and self-renewal through its association with the components of the TGF-β signalling pathway.
- Ravinder K. Bahia
- , Xiaoguang Hao
- & Samuel Weiss
-
Article
| Open AccessPhase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency
Here, Heitmann et al. report results from a Phase I/II trial evaluating CoVac-1, a peptide-based T-cell activator, in patients with B-cell deficiency, demonstrating potent induction of SARS-CoV-2-specific T-cell responses along with a favorable safety profile.
- Jonas S. Heitmann
- , Claudia Tandler
- & Juliane S. Walz
-
Article
| Open AccessResolving the spatial architecture of myeloma and its microenvironment at the single-cell level
The spatial architecture of multiple myeloma remains to be explored. Here, the authors perform bulk and single cell sequencing for samples from newly diagnosed patients and reveal gene signatures associated with focal lesions and spatial heterogeneity in the tumour microenvironment.
- Lukas John
- , Alexandra M. Poos
- & Niels Weinhold
-
Article
| Open AccessGenomic analysis and clinical correlations of non-small cell lung cancer brain metastasis
The genomic landscape of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) remains to be explored. Here, the authors analyse a cohort of 233 patients with BM including 47 primary tumour, 42 extracranial metastatic matched samples and reveal distinct mutational patterns.
- Anna Skakodub
- , Henry Walch
- & Luke R. G. Pike
-
Article
| Open AccessEGFR-targeted fluorescence molecular imaging for intraoperative margin assessment in oral cancer patients: a phase II trial
By using tumor-specific fluorescent tracers, fluorescence molecular imaging (FMI) can be used to visualize tumor tissues with high specificity. Here the authors report the results of a phase II trial to evaluate the diagnostic accuracy of an EGFR-targeted FMI for intraoperative margin assessment in patients with oral squamous cell carcinoma.
- Jaron G. de Wit
- , Jasper Vonk
- & Max J. H. Witjes
-
Article
| Open AccessREPTOR and CREBRF encode key regulators of muscle energy metabolism
Obesity and cancer-induced cachexia are linked to an impairment in the ability of muscle to use glucose or lipids interchangeably as energy substrates. Here, the authors propose that Drosophila REPTOR and its mammalian ortholog CREBRF act as key transcriptional regulators of fuel choice in muscle.
- Pedro Saavedra
- , Phillip A. Dumesic
- & Norbert Perrimon
-
Article
| Open AccessNeoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial
Neoadjuvant chemotherapy followed by gastrectomy is considered standard of care for locally advanced gastric and gastroesophageal junction (G/GEJ) cancers. Here the authors report the results of a phase 2 trial of neoadjuvant sintilimab (anti-PD1) plus chemoradiotherapy in patients with locally advanced G/GEJ tumors.
- Jia Wei
- , Xiaofeng Lu
- & Baorui Liu
-
Article
| Open AccessCopy number architectures define treatment-mediated selection of lethal prostate cancer clones
The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.
- A. M. Mahedi Hasan
- , Paolo Cremaschi
- & Gerhardt Attard
-
Article
| Open AccessCombined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors
It has been previously shown that combining immune checkpoint inhibitors with TGFβ blockade potentiates anti-tumor immune responses. Here the authors show that, in an immune excluded preclinical tumor model, combining therapeutic anti-PD-L1 with anti-TGFβ treatment promotes expansion and differentiation of stem-cell like CD8 + T cells.
- Alessandra Castiglioni
- , Yagai Yang
- & Sören Müller
-
Article
| Open AccessTargeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer
KRAS mutations are associated with an immunosuppressive microenvironment in patients with colorectal cancer (CRC). Here the authors show that knockout of SLC25A22, a mitochondrial glutamate carrier, reverts KRAS-mediated immunosuppression in preclinical CRC models, by suppressing CXCL1 production and impairing MDSC recruitment.
- Qiming Zhou
- , Yao Peng
- & Chi Chun Wong
-
Article
| Open AccessNeoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study
Afatinib is a second-generation EGFR tyrosine kinase inhibitor recommended as the first-line treatment for patients with advanced EGFR mutant non-small cell lung cancer (NSCLC). Here the authors report the results of a phase II clinical trial of neoadjuvant afatinib for stage III EGFR mutant NSCLC.
- Dongliang Bian
- , Liangdong Sun
- & Peng Zhang
-
Article
| Open AccessCombining amino acid PET and MRI imaging increases accuracy to define malignant areas in adult glioma
Magnetic Resonance Imaging (MRI) is normally used to define glioma boundaries for biopsies, surgery and radiotherapy. Here, the authors show that adding FET/PET imaging improves accuracy to define malignant areas of contrast-enhancing gliomas.
- Maciej Harat
- , Józefina Rakowska
- & Bogdan Małkowski
-
Article
| Open AccessA phase 1 study of nivolumab in combination with interferon-gamma for patients with advanced solid tumors
The majority of cancer patients do not respond to single agent immune checkpoint blockade and several combinatorial approaches have now been tested. Here the authors report the results of a phase I dose escalation trial of nivolumab (anti-PD1) in combination with IFN-γ in patients with advanced solid tumors.
- Matthew Zibelman
- , Alexander W. MacFarlane IV
- & Elizabeth R. Plimack
-
Article
| Open AccessEnrichment and sensing tumor cells by embedded immunomodulatory DNA hydrogel to inhibit postoperative tumor recurrence
Decreased survival after surgery is often associated to post-operative tumor recurrence and metastasis. Here the authors describe a DNA hydrogel enabling monitoring of tumor recurrence and spatiotemporally controlled photodynamic immunotherapy to prevent post-operative tumor recurrence and metastasis.
- Danyu Wang
- , Jingwen Liu
- & Kaixiang Zhang
-
Article
| Open AccessSafety and anti-tumour activity of the IgE antibody MOv18 in patients with advanced solid tumours expressing folate receptor-alpha: a phase I trial
IgE antibodies have shown anti-tumor activity, even superior to IgG, in preclinical models. However, all monoclonal antibodies in clinical use for cancer therapy are members of the IgG class. Here the authors report the results of a phase I clinical trial of a chimeric monoclonal IgE antibody, specific for the folate receptor-alpha, in patients with advanced solid cancer.
- James Spicer
- , Bristi Basu
- & Sophia N. Karagiannis
-
Article
| Open AccessCircular RNA encoded MET variant promotes glioblastoma tumorigenesis
MET signalling is required for glioblastoma (GBM) stem cell maintenance. Here the authors identify a circular RNA from the MET gene (circMET) that encodes a MET variant protein (MET404) and show that it can promote GBM tumorigenesis by directly activating the MET receptor independent of HGF stimulation.
- Jian Zhong
- , Xujia Wu
- & Nu Zhang
-
Article
| Open AccessDose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib
Pre-clinical studies have demonstrated the anti-tumor activity of selective inhibitors of CDK7, including samuraciclib. Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti-cancer treatment.
- R. C. Coombes
- , Sacha Howell
- & Matthew G. Krebs
-
Article
| Open AccessThe copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma
‘Treatment resistance is common in ovarian high grade serous carcinoma, often leading to relapse. Here, the authors leverage shallow whole genome and panel sequencing of 276 patients with available diagnostic and relapse samples and show high concordance of copy number and mutation status.
- Philip Smith
- , Thomas Bradley
- & Iain A. McNeish
-
Article
| Open AccessTumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
Here authors show that GDF15, a cytokine that is produced by cancer cells, prevents T cells from extravasation into the tumour microenvironment. Low availability of T cells in GDF-15-expressing tumours thus precludes effective immune therapy.
- Markus Haake
- , Beatrice Haack
- & Jörg Wischhusen
-
Article
| Open AccessComputational analysis of peripheral blood smears detects disease-associated cytomorphologies
While experts analyze cytomorphology to diagnose myelodysplastic syndromes, definitive diagnosis requires complementary information such as karyotype and molecular genetics testing. Here, the authors present a computational method that automatically detects, characterizes and helps identify blood cell characteristics associated with this group of diseases.
- José Guilherme de Almeida
- , Emma Gudgin
- & Moritz Gerstung
-
Article
| Open AccessCirculating trans fatty acids are associated with prostate cancer in Ghanaian and American men
Analyses of the association between fatty acids and prostate cancer have often neglected African patients. Here, the authors analyse 24 circulating fatty acids in Ghanaian, African American, and European American men, and explore the associations with socio-demographic factors, diet, FADS1/2 locus, and prostate cancer.
- Tsion Zewdu Minas
- , Brittany D. Lord
- & Stefan Ambs
-
Article
| Open AccessNuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism
Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.
- Shubhi Srivastava
- , Priyanka Gajwani
- & Jalees Rehman
-
Article
| Open AccessContext-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma
Co-dependency mapping assays have revealed genetic dependencies in cancer and could shed light on chromatin crosstalk mechanisms. Here, the authors establish a pipeline to integrate co-dependency mapping screens with molecular information in pan-cancer cell lines in order to reveal chromatin complexes and potential drug targets.
- Xiao Chen
- , Yinglu Li
- & Chao Lu
-
Article
| Open AccessImpact of TMB/PD-L1 expression and pneumonitis on chemoradiation and durvalumab response in stage III NSCLC
Concurrent chemoradiation and durvalumab is standard of care for stage III non-small cell lung cancer, however, efficacy is variable. Here, the authors show PD-L1 tumor proportion score expression and increased tumor mutational burden are predictive of response and that early-onset pneumonitis leading to durvalumab discontinuation is associated with poor survival.
- Joao V. Alessi
- , Biagio Ricciuti
- & Narek Shaverdian
-
Article
| Open AccessMutational signature dynamics shaping the evolution of oesophageal adenocarcinoma
It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.
- Sujath Abbas
- , Oriol Pich
- & Maria Secrier
-
Article
| Open AccessOxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers
Patients with estrogen receptor positive breast cancer (ER + BC) treated with palbociclib (CDK4/6 inhibitor) frequently develop resistance. Here, the authors identify a reliance of palbociclib resistance on oxidative phosphorylation (OXPHOS) and therapeutically target this vulnerability using an OXPHOS inhibitor, restoring sensitivity in ER + BC preclinical models.
- Rania El-Botty
- , Ludivine Morriset
- & Elisabetta Marangoni
-
Article
| Open AccessDeciphering intercellular signaling complexes by interaction-guided chemical proteomics
Systematic profiling of the indirect cell–cell interactions remains challenging. Here, the authors report a chemical proteomics method to identify ligand-receptor complexes formed between cell surface receptors and secreted proteins from neighboring cells.
- Jiangnan Zheng
- , Zhendong Zheng
- & Ruijun Tian
-
Article
| Open AccessInterventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy
Minimally invasive irreversible electroporation shows some therapeutic promise in irresectable pancreatic cancers that are notorious for poor survival. Here authors combine this with administration of a hydrogel microsphere vaccine that augments the antigen presentation T cell response cascade that naturally initiates following ablation.
- Xiaoyu Liu
- , Yaping Zhuang
- & Zhongmin Wang
-
Article
| Open AccessEngineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization
There are currently a lack of genetic models to study the biology of Uterine fibroids (UFs) tumours. Here the authors precisely engineer cells with mutant MED12 Gly-44 and generate myometrial smooth muscle cells (SMCs) that recapitulate major UFs-like cellular, transcriptional, and metabolic alterations.
- Kadir Buyukcelebi
- , Xintong Chen
- & Mazhar Adli
-
Article
| Open AccessARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade
Loss of the E3 ubiquitin-protein ligase ARIH1 has been associated with cancer escape from anti-tumor immunity. Here the authors show that ARIH1 mediated ubiquitination and degradation of DNA-PKcs trigger activation of STING pathway in tumor cells, sensitizing tumors to immune checkpoint blockade.
- Xiaolan Liu
- , Xufeng Cen
- & Hongguang Xia
-
Article
| Open AccessCancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens
YAP activation is a key driver in both malignant pleural mesothelioma and uveal melanoma through engagement of different regulatory elements. Here, the authors use functional epigenomic analyses to reveal lineage-specific YAP-dependent cistrome.
- Inês A. M. Barbosa
- , Rajaraman Gopalakrishnan
- & Giorgio G. Galli
-
Article
| 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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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