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Structure of the p53 degradation complex from HPV16
HPV’s E6 protein promotes cancer by degrading p53. This study reveals the cryoEM structure of HPV16 E6 in complex with E6AP and p53, highlighting their picomolar affinity and large protein-protein interaction interface.
- John C. K. Wang
- , Hannah T. Baddock
- & Aaron H. Nile
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Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex
Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.
- Fabian Giehler
- , Michael S. Ostertag
- & Arnd Kieser
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Development of mesothelioma-specific oncolytic immunotherapy enabled by immunopeptidomics of murine and human mesothelioma tumors
Malignant pleural mesothelioma is an aggressive cancer with a poor prognosis and limited therapeutic options. Here the authors report the immunopeptidomic landscape of murine and human mesothelioma tumors and demonstrate the anti-tumor potential of oncolytic adenoviruses coated with so-defined tumor-specific peptides in a mouse model of mesothelioma.
- Jacopo Chiaro
- , Gabriella Antignani
- & Vincenzo Cerullo
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Engineered bacterial outer membrane vesicles encapsulating oncolytic adenoviruses enhance the efficacy of cancer virotherapy by augmenting tumor cell autophagy
Oncolytic adenoviruses (Ads)-mediated anti-tumor activity is related to virus-promoted autophagy in tumor cells. Here the authors describe the design of a microbial nanocomposite based on Ads-encapsulated in bacterial outer membrane vesicles to promote Ads intratumoral accumulation and induction of autophagy, promoting anti-tumor immune responses in preclinical cancer models.
- Weiyue Ban
- , Mengchi Sun
- & Jin Sun
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Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer
The role of keratinocyte subpopulations in the different phases of the viral cycle during HPV16 infection remains to be characterised. Here, single cell RNA sequencing of HPV16 infected and uninfected organoids identifies 12 distinct keratinocyte populations including an HPV-reprogrammed keratinocyte subpopulation that is linked to cancer.
- Mary C. Bedard
- , Tafadzwa Chihanga
- & Susanne I. Wells
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Human papillomavirus integration perspective in small cell cervical carcinoma
Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, the authors report human papillomavirus features and genomic landscape in SCCC via high-throughput sequencing methods and identify MYC, SOX, NR4A, ANKRD and CEA family genes as HPV-integrated hotspots.
- Xiaoli Wang
- , Wenlong Jia
- & Shuang Li
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Proteomic analysis reveals key differences between squamous cell carcinomas and adenocarcinomas across multiple tissues
Squamous cell carcinomas are an aggressive cancer type which can occur in multiple organ systems. Here, the authors analyse the proteome of SCC cancers from 17 organs and show commonly dysregulated proteins independent of location.
- Qi Song
- , Ye Yang
- & Yingyong Hou
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A deep learning model and human-machine fusion for prediction of EBV-associated gastric cancer from histopathology
Epstein–Barr virus-associated gastric cancer shows a robust response to immune checkpoint inhibitors. Here the authors introduce a deep convolutional neural network and its fusion with pathologists for predicting it from histopathology.
- Xueyi Zheng
- , Ruixuan Wang
- & Muyan Cai
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Article
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Long-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer
The molecular mechanisms underlying cervical carcinogenesis following integration of HPV DNA into the human genome remain elusive. Here, the authors perform long-read sequencing in 16 HPV16-positive cervical tumors and identify distinct integration types, structural variations and potential driver genes.
- Liyuan Zhou
- , Qiongzi Qiu
- & Yan Lu
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Modelling Chlamydia and HPV co-infection in patient-derived ectocervix organoids reveals distinct cellular reprogramming
Here, Koster et al., model human papillomavirus and Chlamydia coinfection dynamics in patient-derived ectocervical organoids, and characterize the effects of multiple infections in the cellular microenvironment, potentially contributing to neoplasia.
- Stefanie Koster
- , Rajendra Kumar Gurumurthy
- & Cindrilla Chumduri
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EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1
Epstein-Barr virus (EBV)-encoded latent genes are reported to regulate PD-L1 expression to promote immune escape. Here, the authors show that EBV-encoded miRNAs EBV-miR-BART11 and EBV-miR-BART17-3p upregulate PD-L1 expression in nasopharyngeal carcinoma and gastric cancer by targeting FOXP1 and PBRM1.
- Jie Wang
- , Junshang Ge
- & Zhaoyang Zeng
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Kaposi’s sarcoma-associated herpesvirus T cell responses in HIV seronegative individuals from rural Uganda
The T cell response to Kaposi sarcoma-associated herpesvirus is critical to controlling infection and immunopathology but has been poorly explored in immunocompetent patients. Here the authors characterise the T cell response to the Kaposi sarcoma-associated herpesvirus proteome in immunocompetent patients from rural Uganda.
- Angela Nalwoga
- , Romin Roshan
- & Denise Whitby
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Aberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture
Hepatitis B virus (HBV) infection and DNA integration is a frequent cause of hepatocellular carcinoma (HCC), but the consequences of this process are not fully understood. Here the authors use whole-genome and long-read sequencing data from HCC patient samples to study the timing and alterations induced by HBV insertions.
- Eva G. Álvarez
- , Jonas Demeulemeester
- & Jose M. C. Tubio
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Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer
Genetic susceptibility loci for oropharyngeal cancer have been reported but these studies have not always examined human papillomavirus (HPV) status. Here, the authors perform genome-wide analysis taking into account HPV16 serology status and report two independent loci in the HLA region, suggesting the protective role of HLA variants against HPV infection.
- Aida Ferreiro-Iglesias
- , James D. McKay
- & Paul Brennan
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Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape
The genomic characterisation of nasopharyngeal carcinoma (NPC) remains crucial. Here, the authors perform whole-genome sequencing for 70 NPCs with EBV gene expression, report the somatic alterations and EBV-mediated effects converging on NF-κB activation and immune escape and identify targetable homozygous MTAP deletions.
- Jeff P. Bruce
- , Ka-Fai To
- & Kwok-Wai Lo
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Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy
Oncolytic viruses, such as vesicular stomatitis virus (VSV), are a promising class of cancer therapeutics. Here the authors report that a mutation in the CSDE1 gene renders cancer cells resistant to VSV replication and oncolysis, but a mutation-derived escape-associated neoantigen could be exploited for immunotherapy against treatment-resistant tumors.
- Timothy Kottke
- , Jason Tonne
- & Richard G. Vile
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Oncolytic virus-derived type I interferon restricts CAR T cell therapy
Oncolytic viruses promote an inflammatory response and elicit anti-tumor immunity. Here the authors show, unexpectedly, that the oncolytic virus, VSVIFNβ, induces type I interferon responses that, when combined with chimeric antigen receptor (CAR) T therapy, lead to the attrition of both CAR T and conventional T cells, thus dampening their anti-tumor activity.
- Laura Evgin
- , Amanda L. Huff
- & Richard Vile
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p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs
Normal stem cells are maintained by asymmetric cell division, but this process is dysregulated in tumour initiating stem-like cells (TICs). Here, the authors show that TBC1D15 impairs the asymmetric division machinery and activates NOTCH pathway for TIC self-renewal and expansion to promote liver tumorigenesis.
- Hye Yeon Choi
- , Hifzur R. Siddique
- & Keigo Machida
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Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics
NF-κB signalling involves the scaffold protein NEMO, which can be bound by the oncoprotein vFLIP to promote cell survival and oncogenic transformation. Here the authors rationally engineer a tertiary protein mimic of NEMO to disrupt the vFLIP-NEMO interaction to induce cell death.
- Jouliana Sadek
- , Michael G. Wuo
- & Paramjit S. Arora
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Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity
Experimental PVSRIPO oncolytic virus therapy of glioblastoma has shown long-term efficacy in a subset of patients. Here the authors engineer the virus to enable incorporation of tumor-specific antigens, and show proof-of-principle evidence that this modification increases anti-tumor immunity and extends survival in mice.
- Mubeen M. Mosaheb
- , Elena Y. Dobrikova
- & Matthias Gromeier
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Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus
The authors identify circular RNAs (circRNA) from human papillomavirus and show that circRNA-encoded E7 contributes to cancer cell growth in vitro and in tumor xenografts. Furthermore, circE7 is present in TCGA RNA-Seq data from HPV-positive cancers.
- Jiawei Zhao
- , Eunice E. Lee
- & Richard C. Wang
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Exploring the landscape of focal amplifications in cancer using AmpliconArchitect
Focal amplifications are prevalent in many cancer genomes. Here, the authors present AmpliconArchitect (AA), a computational tool for reconstructing their architecture, and reveal an extrachromosomal origin for focal amplifications, including hybrid human-virus elements in HPV-mediated cancers.
- Viraj Deshpande
- , Jens Luebeck
- & Vineet Bafna
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Vasculogenic mimicry formation in EBV-associated epithelial malignancies
EBV latent infection contributes to the pathogenesis of epithelial malignancies by inducing angiogenesis. Here, the authors show EBV promotes vasculogenic mimicry in EBV associated epithelial cancers via AKT/HIF-1α pathway and combination therapy of HIF-1α and VEGF reduces tumour growth.
- Tong Xiang
- , Yu-Xin Lin
- & Lin Feng
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Article
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Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA
HIV patients have an increased risk of developing non-AIDS-defining cancers but the molecular mechanisms underlying this predisposition are unclear. Here the authors show that exosomes secreted by HIV-infected T cells or isolated from the blood of HIV-positive patients, stimulate oncogenic properties of cancer cells through the activation of ERK1/2 signaling pathway.
- Lechuang Chen
- , Zhimin Feng
- & Ge Jin
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Inhibition of the mevalonate pathway enhances cancer cell oncolysis mediated by M1 virus
Oncolytic viruses selectively kill tumour cells and induce anti-tumour immunity. Here, the AUs demonstrate the anti-viral effect of the mevalonate pathway on oncolytic virus M1 in refractory cancer cells and provide evidence for a combination strategy of targeting the mevalonate pathway for potentiating oncolytic virus therapy.
- Jiankai Liang
- , Li Guo
- & Guangmei Yan
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Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis
Human T-cell leukaemia virus type-1 and bovine leukaemia virus infect T and B lymphocytes and lead to aggressive leukaemia. Here, the authors show these proviruses integrate near cancer drivers perturbing transcription termination or antisense RNA-dependent interaction, suggesting post-transcriptional mechanisms in some cases.
- Nicolas Rosewick
- , Keith Durkin
- & Anne Van den Broeke
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Epstein–Barr virus particles induce centrosome amplification and chromosomal instability
Infection with Epstein–Barr virus (EBV) is associated with increased risk of cancer development. Here the authors show that EBV particles, and more specifically the viral protein BNRF1, induce centrosome amplification and chromosomal instability in host cells in the absence of chronic infection.
- Anatoliy Shumilov
- , Ming-Han Tsai
- & Henri-Jacques Delecluse
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Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma
Hepatitis B infection is a risk factor for hepatocellular carcinoma. Here, the authors characterise viral infection in a cohort of hepatocellular carcinoma patients and find viral integration is more frequent in males than females.
- Ling-Hao Zhao
- , Xiao Liu
- & Hong-Yang Wang
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Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells
Epstein–Barr virus (EBV) is involved in the development of some cancers including nasopharyngeal carcinoma. Here, the authors show that a direct interaction between the viral protein gB and a host protein, neuropilin 1, is required for EBV infection of nasopharyngeal epithelial cells.
- Hong-Bo Wang
- , Hua Zhang
- & Mu-Sheng Zeng
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NF-κB-induced KIAA1199 promotes survival through EGFR signalling
The cross-talk between constitutively active EGFR- and NF-κB-dependent pathways in cancer is poorly understood. Here, the authors identify KIAA1199 as a BCL3 and NF-κB-regulated protein that is expressed in cervical lesions and promotes tumorigenesis through Plexin A2 binding and regulation of EGFR stability.
- Kateryna Shostak
- , Xin Zhang
- & Alain Chariot
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Article
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The landscape of viral expression and host gene fusion and adaptation in human cancer
Viruses contribute to the pathogenesis of certain cancers. Using massively parallel sequencing data from The Cancer Genome Atlas to analyse viral expression in 19 tumour types, Tang et al. both confirm and reject previously described viral associations and present new information on viral integration and host interaction.
- Ka-Wei Tang
- , Babak Alaei-Mahabadi
- & Erik Larsson
Structural insights into the functional mechanism of the ubiquitin ligase E6AP