Featured
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Comment
| Open AccessEpigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer
Prostate cancer is a highly heterogeneous disease. Progression on androgen deprivation therapy (ADT) to castration-resistant (CRPC), or neuroendocrine prostate cancer (NEPC), is associated with poor patient survival. This comment highlights recent evidence on the epigenetic mechanisms underlying the emergence of lineage plasticity and neuroendocrine differentiation in treatment-resistant prostate tumors.
- Goutam Chakraborty
- , Kasmira Gupta
- & Natasha Kyprianou
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Article
| Open AccessDeletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy
The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.
- Marcel P. Trefny
- , Nicole Kirchhammer
- & Alfred Zippelius
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Article
| Open AccessGermline T cell receptor exchange results in physiological T cell development and function
The currently available transgenic T cell receptor (TCR) models represent high affinity antigen-TCR interactions. Authors here present an alternative approach to target an exogenous TCR into the physiological Trac locus in the germline of mice, which uncovers that the natural genomic context for TCRs can enhance the antigen sensitivity of lower affinity TCRs and enables the physiologic range of antigen-TCR interaction and a gene dosage dependent mechanism of central tolerance.
- Meagan R. Rollins
- , Jackson F. Raynor
- & Ingunn M. Stromnes
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Comment
| Open AccessA two-faced selectivity solution to target SMARCA2 for cancer therapy
Two new studies exploring PROTAC-mediated degradation of SMARCA2 for cancer therapy solve an apparently intractable selectivity challenge with SMARCA4 by utilising the requirement for a productive ternary complex between the protein, PROTAC and ligase complex.
- John D. Harling
- & Christopher P. Tinworth
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Article
| Open AccessEnhancing CAR-T cell functionality in a patient-specific manner
‘Manufacturing CAR-T cells is a streamlined and highly regulated procedure involving T-cell-expansion and activation on a standardised platform. Here, the authors show that a personalized approach, taking the phenotypic attributes of individual patients’ T cells into account, leads to more efficient CAR-T cell manufacturing and better CAR-T cell functionality.
- David K. Y. Zhang
- , Kwasi Adu-Berchie
- & David J. Mooney
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Article
| Open AccessProteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms
The proteogenomic landscape of diffuse gliomas remains to be explored. Here, the authors perform proteogenomic characterisation of diffuse gliomas, investigate the functional role of genomic alterations and suggest three proteomic subgroups.
- Yunzhi Wang
- , Rongkui Luo
- & Chen Ding
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Article
| Open AccessCellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma
Senescence can have beneficial and detrimental impact on cancer progression depending on the cellular context. Here the authors show that NRF2 regulates the senescence phenotype in malignant cells which consequently contribute to glioblastoma progression.
- Rana Salam
- , Alexa Saliou
- & Isabelle Le Roux
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Article
| Open AccessThe NFIB/CARM1 partnership is a driver in preclinical models of small cell lung cancer
Protein arginine methylation can contribute to tumor progression. Here the authors show that protein arginine methyltransferase, CARM1, methylates transcription factor NFIB to promote the growth of small cell lung cancers.
- Guozhen Gao
- , Simone Hausmann
- & Mark T. Bedford
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Article
| Open AccessEpigenomic charting and functional annotation of risk loci in renal cell carcinoma
The epigenomic landscape of renal cell carcinoma (RCC) remains to be explored. Here, integrative epigenomic analysis of primary human RCC samples and RCC GWAS risk SNPs identifies transcription-factor specific subtypes and enrichment of risk variants in allelically-imbalanced peaks.
- Amin H. Nassar
- , Sarah Abou Alaiwi
- & Matthew L. Freedman
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Article
| Open AccessTumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation
YTHDF1 is an m6A reader that binds to methylated RNA and facilitates translation. Here the authors show that tumor intrinsic YTHDF1 promotes tumorigenesis by regulating lysosomal proteolysis of MHC-I and that YTHDF1 targeting boosts anti-tumor immunity and response to immunotherapy in preclinical cancer models.
- Wanzun Lin
- , Li Chen
- & Jiade J. Lu
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Article
| Open AccessNiche stiffness sustains cancer stemness via TAZ and NANOG phase separation
Stromal cells in the tumour microenvironment are reported to regulate cancer stemness via biomechanical signals. Here the authors show that TAZ activated by biomechanical cues enhanced cancer stem cell properties via phase separation with Nanog.
- Xinwei Liu
- , Yingying Ye
- & Qiyi Zhao
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Article
| Open AccessIntegrative analysis of multiple genomic data from intrahepatic cholangiocarcinoma organoids enables tumor subtyping
There is still need for representative models of intrahepatic cholangiocarcinoma (ICC) subtypes. Here, the authors develop organoids for two recently suggested ICC subtypes and identify distinct transcriptional profiles and potential therapeutic targets.
- Hee Seung Lee
- , Dai Hoon Han
- & Jun Yong Park
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Article
| Open AccessA comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer
T cell exhaustion in breast tumours remains to be fully characterised. Here, single cell transcriptomics and imaging mass cytometry analysis of luminal breast tumours with or without exhausted T cells suggests distinct patterns of PD-1 and CXCL13 expression in T cells, and of MHC-I, but not PD-L1, expression in tumour cells.
- Sandra Tietscher
- , Johanna Wagner
- & Bernd Bodenmiller
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Article
| Open AccessGermline TP53 mutations undergo copy number gain years prior to tumor diagnosis
Li-Fraumeni syndrome (LFS) is associated with pathogenic germline TP53 variants and predisposes patients to cancer; understanding the evolution and drivers of LFS-related tumours remains crucial. Here, the authors analyse 22 LFS tumours using whole-genome sequencing and reconstruct the evolution and timing of somatic driver alterations.
- Nicholas Light
- , Mehdi Layeghifard
- & Adam Shlien
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Article
| Open AccessNeoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer
Immune checkpoint inhibitors and antiangiogenic agents have shown some activity in patients with late-stage gastric cancer. Here the authors report the results of a phase II trial of neoadjuvant anti-PD1 (camrelizumab), antiangiogenic agent (apatinib), and chemotherapy (S-1 ± Oxaliplatin) in stage T4a/bN + M0 gastric cancer patients.
- Song Li
- , Wenbin Yu
- & Lian Liu
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Article
| Open AccessA pH-responsive T1-T2 dual-modal MRI contrast agent for cancer imaging
Magnetic resonance imaging (MRI) is a well-established non-invasive medical imaging technology. Here, to improve the performance of the technique, the authors describe the design of a pH-responsive T1-T2 dual-modal MRI contrast agent, showing enhanced imaging sensitivity in preclinical cancer models.
- Hongwei Lu
- , An Chen
- & Leilei Tian
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Article
| Open AccessEstimating diagnostic uncertainty in artificial intelligence assisted pathology using conformal prediction
Artificial intelligence prediction accuracy can be reduced with new data. Here, the authors utilise conformal prediction to reduce incorrect predictions in histopathological analysis of prostate cancer biopsies.
- Henrik Olsson
- , Kimmo Kartasalo
- & Martin Eklund
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Article
| Open AccessTumor fractions deciphered from circulating cell-free DNA methylation for cancer early diagnosis
‘Circulating cell-free DNA can be used to predict cancer, but it is more challenging to assess in early stage cancer. Here, the authors created a diagnostic model using tumor fractions deciphered from circulating cfDNA methylation signatures, which exhibited an 86% sensitivity in detecting early-stage cancer.
- Xiao Zhou
- , Zhen Cheng
- & Weibin Cheng
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Article
| Open AccessBrain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer
While EGFR-targeted therapies have clinical benefit, drug-resistant brain metastases present a major obstacle. Here, the authors identify a genetic signature in brain metastatic lesions associated with osimertinib resistance and find RhoA to have an important role in the resulting phenotype.
- Sally J. Adua
- , Anna Arnal-Estapé
- & Don X. Nguyen
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Article
| Open AccessA multicenter phase 2 trial of camrelizumab plus famitinib for women with recurrent or metastatic cervical squamous cell carcinoma
Patients with recurrent or metastatic cervical cancer have limited therapeutic options. Here the authors report efficacy and safety of camrelizumab (anti-PD-1 antibody) in combination with famitinib (anti-angiogenic agent) in pre-treated recurrent or metastatic squamous cervical cancer.
- Lingfang Xia
- , Qi Zhou
- & Xiaohua Wu
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Article
| Open AccessLY6D marks pre-existing resistant basosquamous tumor subpopulations
The identification of distinct cell populations with cellular plasticity in skin basal cell carcinoma is important for understanding treatment resistance mechanisms. Here, the authors identify the resistant LY6D+ basosquamous population that correlates with poor clinical outcomes.
- Daniel Haensel
- , Sadhana Gaddam
- & Anthony E. Oro
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Article
| Open AccessProteogenomic characterization of MiT family translocation renal cell carcinoma
The molecular landscape of microphthalmia transcription factor family translocation renal cell carcinoma tumours remain to be characterised. Here, the authors perform proteogenomic analysis and reveal dysregulation of DNA repair, mTOR signalling and metabolic processes.
- Yuanyuan Qu
- , Xiaohui Wu
- & Chen Ding
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Article
| Open AccessGenetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers
Acquired resistance can be associated with genetic changes, however, clinical molecular profiling is usually only considered at the time of diagnosis. Here, the authors use serial ctDNA profiling of 449 gastrointestinal cancers to demonstrate widespread tumour evolution associated with treatment resistance and its potential implications for treatment.
- David Hsiehchen
- , Leslie Bucheit
- & Hao Zhu
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Article
| Open AccessEngineered Lactococcus lactis secreting Flt3L and OX40 ligand for in situ vaccination-based cancer immunotherapy
The probiotic Lactococcus lactis has been used for the delivery of therapeutic molecules. Here the authors engineer Lactococcus lactis to express a fusion protein of Flt3L and OX40 ligand, eliciting anti-tumor immune response in preclinical cancer models.
- Junmeng Zhu
- , Yaohua Ke
- & Baorui Liu
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Article
| Open AccessExtensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential
Epigenetic reprogramming of the androgen receptor (AR) has been identified as an important process driving prostate cancer (PCa) progression. Here, the authors analyze the role of AR chromatin binding heterogeneity in PCa clinical outcomes, metastasis and relapse.
- Jeroen Kneppers
- , Tesa M. Severson
- & Wilbert Zwart
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Article
| Open AccessInflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer
Inflammatory conditions often affect colorectal cancer patients, and their effect on their ongoing treatment is a pressing medical question. Here authors show that inflammation interferes with local anti-tumour immune response and inhibits response to immune checkpoint blockade therapy via immunosuppressive neutrophil leukocytes.
- Qiaoqi Sui
- , Xi Zhang
- & Pei-Rong Ding
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Article
| Open AccessA single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma
Studying the cell composition of acral melanoma at the single-cell level could provide some clues about its poor response to immunotherapy. Here, the authors analyse acral and cutaneous melanoma patient samples using single-cell RNA-sequencing, and reveal a severe immunosuppressive state in acral melanomas
- Chao Zhang
- , Hongru Shen
- & Jilong Yang
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Article
| Open AccessEvaluating cancer etiology and risk with a mathematical model of tumor evolution
Modelling how endogenous mutations accumulate in tissues is valuable to understand how cancers develop and evolve. Here, the authors establish a mathematical model that can predict the number of endogenous somatic mutations in the lifetime of tissues and approximate the time to cancer development.
- Sophie Pénisson
- , Amaury Lambert
- & Cristian Tomasetti
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Article
| Open AccessGenomic disparities between cancers in adolescent and young adults and in older adults
The biological underpinnings underlying the increased mortality and morbidity in adolescents and young adults (AYA) remains poorly understood. Here, the authors investigate the clinical and genomic disparities in AYA and older adults in a cohort of more than 100,000 cancer patients.
- Xiaojing Wang
- , Anne-Marie Langevin
- & Siyuan Zheng
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Article
| Open AccessInflammatory bone marrow signaling in pediatric acute myeloid leukemia distinguishes patients with poor outcomes
IL6 expression in the bone marrow is associated with reduced survival in paediatric AML. Here, the authors used RNA-seq to identify treatment resistance-associated co-occurring inflammatory signalling in leukemic cells.
- Hamid Bolouri
- , Rhonda E. Ries
- & Soheil Meshinchi
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Article
| Open AccessMulti-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment
Osteosarcoma survival rates have been largely unchanged for several decades, and treatment response is variable. Here, the authors analyzed genomic, transcriptomic and epigenomic data from 121 osteosarcoma patients and identify subtypes related to treatment outcome.
- Yafei Jiang
- , Jinzeng Wang
- & Yingqi Hua
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Article
| Open AccessExpanding cross-presenting dendritic cells enhances oncolytic virotherapy and is critical for long-term anti-tumor immunity
Strategies to advance T cell based immune therapies are mostly focusing on the improvement of CD8 T cell effector functions, such as cytotoxicity or recruitment to the tumor. Here authors show that by combining in situ vaccination with oncolytic Newcastle Disease Virus and Flt3L-driven dendritic cell expansion, the anti-tumor T cell response is amplified via increased antigen cross-presentation.
- Judit Svensson-Arvelund
- , Sara Cuadrado-Castano
- & Joshua D. Brody
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Article
| Open AccessSomatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer
Evolutionary principles could help distinguish driver from passenger mutations in cancer. Here, the authors develop SEISMIC, a method to identify cancer driver genes based on their deviation from expected mutation status patterns across a cohort under neutral evolution, and find potential drivers in melanoma and other cancer types.
- Martin Boström
- & Erik Larsson
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Article
| Open AccessElective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors
Neck dissection and/or elective nodal irradiation (ENI) are commonly performed in patients with head and neck squamous cell carcinoma (HNSCC) to minimize local and regional recurrence. However, here the authors show that ENI blunts the immune response to combined radiation and immunotherapy, increasing local and distant tumor growth in HNSCC preclinical models.
- Laurel B. Darragh
- , Jacob Gadwa
- & Sana D. Karam
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Article
| Open AccessFirst-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors
PIK3CA is a commonly mutated cancer-associated gene, making it an attractive therapeutic target. Here, the authors report the results of a first-in-human phase Ia trial to assess the safety and recommended phase II dose of CYH33, a PI3Kα inhibitor, in patients with advanced solid tumors.
- Xiao-Li Wei
- , Fu-Rong Liu
- & Rui-Hua Xu
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Article
| Open AccessInhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance
Immune checkpoint blockade is showing promise in cancer immune therapy, but many solid tumours are resistant. Authors here identify a pathway in T cells that leads to increased activity of C-terminal Src kinase, a negative regulator of T cell activity, thus disabling tumour infiltrating T cells and causing immune therapy resistance.
- Dhivya Sridaran
- , Surbhi Chouhan
- & Nupam P. Mahajan
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Article
| Open AccessSingle cell profiling of primary and paired metastatic lymph node tumors in breast cancer patients
Lymph node metastasized tumours (LNMT) in breast cancer have not been comprehensively characterised. Here, the authors perform single cell RNA sequencing analysis of paired primary and LNMT breast cancer samples and suggest a more immunosuppressive tumour microenvironment in the latter.
- Tong Liu
- , Cheng Liu
- & Hongquan Zhang
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Article
| Open AccessThe Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction
Surgery is an important part of treatment for gastric adenocarcinoma, however, the consensus on perioperative care is less clear. Here, the authors report the results of a phase II clinical trial investigating neoadjuvant camrelizumab with concurrent chemoradiotherapy, followed by surgery for the treatment of advanced gastric adenocarcinoma.
- Zhaoqing Tang
- , Yan Wang
- & Yihong Sun
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Article
| Open AccessAn mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.
- Kaushal Asrani
- , Juhyung Woo
- & Tamara L. Lotan
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Article
| Open AccessSystematic characterization of cancer transcriptome at transcript resolution
Modification of transcribed mRNAs enables regulation of transcription but its extent in cancer cells is incompletely understood. Here, the authors analyse transcript assembly in over 1000 cancer cell lines and find unannotated transcripts are common, and are associated with drug sensitivity.
- Wei Hu
- , Yangjun Wu
- & Shengli Li
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Article
| Open AccessSingle-cell profiling reveals a memory B cell-like subtype of follicular lymphoma with increased transformation risk
Follicular lymphoma can transform to a more aggressive histology. Here, the authors use bulk and single cell analysis to create a 26 marker panel which could be used to profile FL samples and predict the risk of transformation using flow cytometry.
- Xuehai Wang
- , Michael Nissen
- & Andrew P. Weng
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Article
| Open AccessSpatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival
Characterisation of molecular heterogeneity in glioblastoma would improve patient stratification. Here, the authors integrate spatial proteomics and clinical data from glioblastoma patients and identify 3 molecular groups and a 5-protein signature that was associated with survival.
- Marie Duhamel
- , Lauranne Drelich
- & Michel Salzet
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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 AccessFOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis
Forkhead box transcription factor, FOXQ1 is reported to promote epithelial-mesenchymal transition (EMT) and cancer metastasis. Here the authors show that FOXQ1 recruits the KMT2/MLL histone methyltransferase complex as a transcriptional coactivator to activate EMT programme in breast cancer.
- Allison V. Mitchell
- , Ling Wu
- & Guojun Wu
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Article
| Open AccessMIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia
The links between DNA methylation and gene expression are poorly understood on large-scale. Here the authors show that MIR retrotransposons within introns can play this role in acute myeloid leukemia harbouring mutations in epigenetic modifiers.
- Aristeidis G. Telonis
- , Qin Yang
- & Maria E. Figueroa
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Article
| Open AccessTargeting vasoactive intestinal peptide-mediated signaling enhances response to immune checkpoint therapy in pancreatic ductal adenocarcinoma
Poor antitumor response of pancreatic cancer to immunotherapies is a major barrier to effective disease management. Herein we show that pancreatic cancers overexpress vasoactive intestinal peptide, and pharmacological inhibition of its signaling significantly enhances responsiveness of pancreatic ductal adenocarcinoma to immune checkpoint therapy, thus improving overall survival in mouse models.
- Sruthi Ravindranathan
- , Tenzin Passang
- & Edmund K. Waller
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Article
| Open AccessClonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma. Here we show that identification of clonal somatic copy number alterations in frequently amplified cancer genes could inform therapeutics for precision medicine.
- Filipe Correia Martins
- , Dominique-Laurent Couturier
- & James D. Brenton
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Article
| Open AccessEnhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response
Activation of ESCRT-mediated cell membrane repair can reduce the extent of tumor cell pyroptosis. Here the authors develop two formulations (an injectable hydrogel and a cell patch) for the sustained release of a Gasdermin-D bacteria-based delivery system and of biodegradable nanoparticles loaded with an ESCRT inhibitor, triggering pyroptosis and antitumor immune responses in preclinical cancer models.
- Zhaoting Li
- , Fanyi Mo
- & Quanyin Hu