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| Open AccessSpatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Spatial positioning of cells within the tumour microenvironment may have a function in the success of immune checkpoint immunotherapy (ICI). Here the authors analyse spatial relationships from immunohistochemistry samples prior to ICI therapy and show that CD8 T cell or macrophage proximity to cancer cells is associated with better responses.
- Alberto Gil-Jimenez
- , Nick van Dijk
- & Lodewyk F. A. Wessels
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Article
| Open AccessThe evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis
Detailed molecular studies are required to understand the differences between primary and metastatic upper tract urothelial carcinoma (UTUC). Here, the authors use genomics, transcriptomics and imaging mass cytometry to characterise the molecular profiles of primary and metastatic UTUC, and find that molecular subtypes remain highly conserved.
- Kentaro Ohara
- , André Figueiredo Rendeiro
- & Juan Miguel Mosquera
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| Open AccessThe IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer
SMARCB1 is frequently lost in solid cancer and reported to support tumourigenesis through STAT3 activation. Here, the authors show in several preclinical models that targeting IL6/JAK/STAT3 molecular pathway is a potential therapeutic approach for SMARCB1-deficient bladder cancer.
- Chandra Sekhar Amara
- , Karthik Reddy Kami Reddy
- & Nagireddy Putluri
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Article
| Open AccessReconstructing disease dynamics for mechanistic insights and clinical benefit
Understanding disease progression dynamics is critical for diagnostics and treatment, but capturing dynamics is difficult. Here, the authors present a method for modelling disease progression from high dimensional molecular data that enables patient stratification and high-risk disease state identification, showcased in bladder cancer.
- Amit Frishberg
- , Neta Milman
- & Shai S. Shen-Orr
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Article
| Open AccessProteogenomics of different urothelial bladder cancer stages reveals distinct molecular features for papillary cancer and carcinoma in situ
Urothelial bladder cancer (UC) progression occurs as a multi-step process that leads to different kinds of lesions and subtypes. Here, the authors characterise benign and invasive lesions that occur during UC progression using proteogenomics in patient samples and show critical molecular pathways and prognostic associations.
- Zhenmei Yao
- , Ning Xu
- & Chen Ding
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Article
| Open AccessAhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer
An effective response to chemotherapy is often associated with the promotion of type-I interferons and anti-tumor immune responses. Here the authors show that tryptophan metabolites induced by chemo-drugs interfere with STING activation and IFN-I production in bladder cancer, reducing the efficacy of chemotherapy.
- Zikun Ma
- , Zhiyong Li
- & Xiaoyu Liang
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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 AccessExpression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer
The response to checkpoint immunotherapy within bladder cancer patients is highly variable. Here, the authors use RNA-seq, ATAC-seq and digital spatial profiling of pre- and post-treatment samples from the PURE01 trial to identify subtypes associated with treatment response.
- A. Gordon Robertson
- , Khyati Meghani
- & Joshua J. Meeks
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Article
| Open AccessBladder cancer organoids as a functional system to model different disease stages and therapy response
Bladder cancer heterogeneity can limit treatment efficacy in individual patients. Here, the authors use patient derived organoids to develop a drug screening pipeline and identify markers of treatment response.
- Martina Minoli
- , Thomas Cantore
- & Marianna Kruithof-de Julio
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Article
| Open AccessSingle cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment
The molecular mechanisms underlying tumour heterogeneity in bladder cancer remain to be explored. Here, the authors perform single cell RNA sequencing and identify CD39 as a potential target for immunotherapy, which they validate in vivo.
- Lilong Liu
- , Yaxin Hou
- & Ke Chen
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Article
| Open AccessCollaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer
The Bladder Cancer Advocacy Network established the UC-GENOME study in order to create a biobank and data repository for metastatic urothelial carcinoma. Here, the authors present the first characterization and analysis of DNA and RNA sequencing data from the 218 patients included in the UC-GENOME.
- Jeffrey S. Damrauer
- , Wolfgang Beckabir
- & Matthew I. Milowsky
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Article
| Open AccessFOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation
Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity.
- Joshua I. Warrick
- , Wenhuo Hu
- & Hikmat A. Al-Ahmadie
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Article
| Open AccessTargeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus
Neither CDK4/6 inhibitors nor oncolytic adenoviruses show high efficiency as monotherapy in the treatment of cancer. Authors show here that when combined, CDK4/6 inhibitors deplete Retinoblastoma protein levels, which leads to more efficient virus replication and an increase in oncolytic virus-producing cancer cells and thus to efficient anti-tumor response in mouse xenograft sarcoma models.
- Jana Koch
- , Sebastian J. Schober
- & Per Sonne Holm
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Article
| Open AccessNetwork-based machine learning approach to predict immunotherapy response in cancer patients
Identifying biomarkers for response to immunotherapy in cancer remains challenging. Here, the authors develop an approach based on network biology and machine learning -NetBio- to identify molecular biomarkers of response to immunotherapy across different cancer types and cohorts.
- JungHo Kong
- , Doyeon Ha
- & Sanguk Kim
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Article
| Open AccessTRMT6/61A-dependent base methylation of tRNA-derived fragments regulates gene-silencing activity and the unfolded protein response in bladder cancer
RNA modifications are important regulators of RNA biology. Here we report N1-methyladenosine (m1A) enrichment on 22-nucleotide tRNA fragments and its effect on gene-silencing. Higher level of m1A in bladder cancer is accompanied by gene dysregulation in unfolded protein response.
- Zhangli Su
- , Ida Monshaugen
- & Anindya Dutta
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Article
| Open AccessNeoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma
Immune checkpoint blockade therapy is successful in a high proportion of cancer patients, but others remain unresponsive. Authors here show that therapeutic success might be predictable in metastatic bladder cancer by longitudinal analysis of the early neoantigen-specific CD8 T cell response in peripheral blood.
- Jeppe Sejerø Holm
- , Samuel A. Funt
- & Sine Reker Hadrup
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Article
| Open AccessPredictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial
Identification of biomarkers to stratify patients who might benefit from treatment is needed to optimize targeted therapies. Here, based on an analysis of the RANGE trial (NCT02426125), the authors report potentially predictive biomarkers for survival benefit in patients with platinum-refractory advanced urothelial carcinoma treated with the anti-VEGFR2 monoclonal antibody ramucirumab.
- Michiel S. van der Heijden
- , Thomas Powles
- & Alexandra Drakaki
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Article
| Open AccessMTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers
The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when comparing to MTAP-proficient UC patients.
- Omar Alhalabi
- , Jianfeng Chen
- & Jianjun Gao
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Article
| Open AccessCell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors
Chemoimmunotherapy recently failed to improve objective response for patients with advanced muscle-invasive bladder cancer (MIBC). Here using two murine models of immune-excluded MIBC, the authors show that resistance to chemoimmunotherapy can be overcome by blocking the COX-2/prostaglandin E2 axis, reinvigorating anti-tumor immune responses.
- Fotis Nikolos
- , Kazukuni Hayashi
- & Keith Syson Chan
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Article
| Open AccessPparg signaling controls bladder cancer subtype and immune exclusion
PPARg is differentially expressed in bladder cancer subtypes. Here, the authors show in mice that when an activated form of PPARg is expressed in basal bladder cells tumours do not form, however in the presence of injury the basal cells differentiate into luminal cells.
- Tiffany Tate
- , Tina Xiang
- & Cathy Lee Mendelsohn
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Article
| Open AccessAn N-Cadherin 2 expressing epithelial cell subpopulation predicts response to surgery, chemotherapy and immunotherapy in bladder cancer
The identification of response biomarkers for surgery, chemotherapy and immune checkpoint therapy in bladder cancer is crucial. Here, single nuclei RNA sequencing and spatial profiling identify a cancer cell population expressing Neural Type Cadherin 2 that associates with distinct treatment outcomes.
- Kenneth H. Gouin III
- , Nathan Ing
- & Dan Theodorescu
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Matters Arising
| Open AccessReconciling differences in impact of molecular subtyping on response to cisplatin-based chemotherapy
- Mathieu Roumiguie
- , Alberto Contreras-Sanz
- & Peter C. Black
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Article
| Open AccessRole of neutrophil extracellular traps in radiation resistance of invasive bladder cancer
Radioresistance remains a challenge in the treatment of bladder cancer. In this study, the authors show in mice that radiation increases deposits of neutrophil extracellular traps (NETs) via a TLR4-dependent mechanism and that NETs-targeting strategies can improve the response to radiotherapy.
- Surashri Shinde-Jadhav
- , Jose Joao Mansure
- & Wassim Kassouf
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Article
| Open AccessAn integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer
Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.
- Sia Viborg Lindskrog
- , Frederik Prip
- & Lars Dyrskjøt
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Article
| Open AccessDominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis
The human chromosome locus 9p21.3 is a tumour suppressor hub which encodes three CDK inhibitors, p15INK4B, p14ARF and p16INK4A. Here, the authors show that p15INK4B inhibits the cell cycle and glycolysis in a murine model of HRas + ‐mediated urothelial carcinoma and has a more relevant role as a tumour suppressor than its neighbouring p16INK4A.
- Yong Xia
- , Yan Liu
- & Xue-Ru Wu
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Article
| Open AccessPlasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer
In metastatic urothelial carcinoma, it has not been established whether circulating tumor DNA (ctDNA) can replace archival primary tissue to assess mutations and biomarkers. Here, the authors show high mutation concordance between ctDNA and tumour tissue, with high consistency in serial samples.
- Gillian Vandekerkhove
- , Jean-Michel Lavoie
- & Alexander W. Wyatt
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Article
| Open AccessTipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death
Most chemotherapeutic agents, including gemcitabine, do not elicit immunogenic cell death, a phenomenon associated with the release of damage-associated molecule patterns (DAMPs). Here, the authors show that gemcitabine-treated dying cancer cells express hallmark DAMPs but their immunogenic properties are hindered by the concomitant release of the inhibitory DAMP PGE2.
- K. Hayashi
- , F. Nikolos
- & K. S. Chan
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Article
| Open AccessCommon germline-somatic variant interactions in advanced urothelial cancer
The role of germline variation in human cancers is not fully understood. Here, the authors define the landscape of putative deleterious germline variants that abrogate tumor suppressor proteins in advanced urothelial cancer patients.
- Aram Vosoughi
- , Tuo Zhang
- & Bishoy M. Faltas
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Article
| Open AccessSingle-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma
Bladder urothelial carcinoma is one of the most prevalent urogenital cancer types with limited therapeutic options. Here, the authors characterize the tumor immune microenvironment of bladder cancer using single cell RNA sequencing and suggest a role for inflammatory cancer-associated fibroblasts in tumor progression.
- Zhaohui Chen
- , Lijie Zhou
- & Ke Chen
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Article
| Open AccessEpithelial plasticity can generate multi-lineage phenotypes in human and murine bladder cancers
Recent studies have utilized bulk tumour mRNA sequencing to classify bladder cancers into distinct subgroups. Here, the authors use single cell transcriptomic analysis and cell transplant studies to show that epithelial plasticity can generate basal, luminal and mesenchymal phenotypes in human and murine bladder cancers.
- John P. Sfakianos
- , Jorge Daza
- & David J. Mulholland
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Article
| Open Accessc-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression
HGF/c-MET upregulation is frequent in bladder cancer. Here, the authors show that HGF induces EMT and invasion by stabilising TGFβ receptor through inhibition of the SMURF2 ligase, and the combined blockade of MAPK and TGFβ pathways suppresses HGF-mediated bladder cancer progression.
- Wen Jing Sim
- , Prasanna Vasudevan Iyengar
- & Jean Paul Thiery
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Article
| Open AccessUpper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling
Upper tract urothelial carcinoma (UTUC) is an aggressive cancer and largely uncharacterised cancer. Here, Faltas and colleagues report its distinctive molecular and immune landscape compared to urothelial carcinoma of the bladder and explore the role of FGFR3 signaling in UTUC biology.
- Brian D. Robinson
- , Panagiotis J. Vlachostergios
- & Bishoy M. Faltas
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Article
| Open AccessCollagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung
Collagen is a dynamic component of both the tumor and metastatic niche. Here, the authors show that airway smooth muscle cells are a collagen III rich niche bladder cancer cells expressing CD167a, and Stat3 is a downstream target for abrogating these collagen III/CD167a-driven metastatic foci.
- Yu-Cheng Lee
- , Antonina V. Kurtova
- & Keith Syson Chan
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Article
| Open AccessWhole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer
Bladder cancer is one of the most common and highly vascularized cancers. Here the authors perform a whole-genome analysis in urothelial bladder carcinomas and identify recurrent genetic alterations in a set of angiogenesis genes, facilitating the understanding of molecular mechanisms underlying pathological angiogenesis in this type of cancer.
- Song Wu
- , Tong Ou
- & Zhiming Cai
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Article
| Open AccessRecurrent activating mutations of PPARγ associated with luminal bladder tumors
Activation of the PPARγ/RXRα pathway in luminal bladder cancers has mainly been linked to PPARG gene amplifications and activating point mutations in RXRα. Here, the authors identify recurrent PPARγ mutations with similar effects and elucidate the structural basis for this mutational PPARγ activation.
- Natacha Rochel
- , Clémentine Krucker
- & Isabelle Bernard-Pierrot
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Article
| Open AccessMutational patterns in chemotherapy resistant muscle-invasive bladder cancer
The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.
- David Liu
- , Philip Abbosh
- & Eliezer M. Van Allen
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Article
| Open AccessInterdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy
Combination therapy with α-CTLA-4 and α-PD-1 is showing improved therapeutic effects in clinical trials. Here, the authors report that mechanistically in bladder cancer such effect depends upon an upregulation of T cell activity mediated by the IL-7/IL-7R and IFN-γ/IFN-γR signalling pathways.
- Lewis Zhichang Shi
- , Tihui Fu
- & Padmanee Sharma
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Article |
Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells
Tools derived from synthetic biology offer powerful means to refine drug delivery and disease detection. Liu et al. engineer a logical AND gate using CRISPR-Cas9 to drive gene expression only cells in which two promoters are active, and use it to selectively inhibit the growth of bladder cancer cells in vitro.
- Yuchen Liu
- , Yayue Zeng
- & Zhiming Cai
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Article
| Open AccessWhole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden
Bladder cancer is a complex genetic disease and a common cause of death due to malignancy. Here, the authors carry out whole-genome sequencing of 14 bladder cancers to characterize the genomic landscape of the disease and show that mutational burden is associated with tumour progression in these samples.
- J. -B. Cazier
- , S. R. Rao
- & F. C. Hamdy