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| Open AccessCoadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) cells can utilise the tumour microenvironment to metastasise to the liver. Here the authors show that hepatoctyes overexpress SLIT2 to enable premetastatic niche formation for ROBO1-positive PDAC cells to support the survival of these tumour cells in the liver.
- Qing Li
- , Xiao-Xin Zhang
- & Zhi-Gang Zhang
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Article
| Open AccessSingle-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis
Peritoneal metastasis is one of the most common forms of death for gastrointestinal cancers, however, its cell composition is incompletely understood. Here, the authors use single cell RNA-seq of peritoneal metastases from 35 patients and show diversity in immune cells, and plasticity in cancer cell phenotypes and autophagy related genes as biomarkers of prognosis.
- Xuan-Zhang Huang
- , Min-Jiao Pang
- & Zhen-Ning Wang
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Article
| Open AccessMultilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer
The molecular differences between the two major gastric cancer subtypes diffuse-type gastric cancer (DGC) and intestinaltype gastric cancer (IGC) remain to be investigated. Here, integrated analysis of proteome, phospho-proteome and transcription factor activity for DGC and IGC reveals potential subtypes.
- Wenhao Shi
- , Yushen Wang
- & Chen Ding
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Article
| Open AccessSingle-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
The role of therapy in shaping the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) remains to be explored. Here, the authors perform single-cell RNA sequencing in PDAC samples before and after chemotherapy and suggest that chemotherapy may promote resistance to immunotherapy.
- Gregor Werba
- , Daniel Weissinger
- & Diane M. Simeone
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Article
| Open AccessIntegrative proteomic characterization of adenocarcinoma of esophagogastric junction
The molecular subtypes of adenocarcinoma of the esophagogastric junction (AEG) remain to be identified. Here, the authors perform proteogenomic characterisation of AEG tumours with paired normal adjacent tissues and suggest three proteomic subtypes and potential druggable targets.
- Shengli Li
- , Li Yuan
- & Xiang-Dong Cheng
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Article
| Open AccessFGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells
Glioblastoma is an aggressive type of cancer with poor patient prognosis. Here, the authors show that T cells armed with an FGL2-specific scFV can induce antitumour responses mediated by tissue-resident memory T cells in the brain.
- Qingnan Zhao
- , Jiemiao Hu
- & Shulin Li
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Article
| Open AccessLong-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.
- Jenniffer Linares
- , Anna Sallent-Aragay
- & Alexandre Calon
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Article
| Open AccessBile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer
Non-enterotoxigenic Bacteroides fragilis (NTBF) is abundant in colorectal cancer (CRC) patients and in a high-fat diet (HFD)-induced CRC model. Here the authors show that bile salt hydrolase-expressing NTBF is enriched in CRC patients with overweight and promotes tumor growth in an HFD-induced CRC mouse model.
- Lulu Sun
- , Yi Zhang
- & Frank J. Gonzalez
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Article
| Open AccessLoss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability
Group 3 medulloblastomas (MBs) have the worst prognosis amongst the subtypes of MBs and are associated with MYC amplifications. Here the authors identify that mutations in CTDNEP1 cause MYC activation, amplification, and genomic instability in this subtype of MBs.
- Zaili Luo
- , Dazhuan Xin
- & Q. Richard Lu
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Article
| Open AccessMitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells
DNA replication stress can generate under-replicated DNA regions which is fixed by an atypical form of DNA repair synthesis in mitosis (MiDAS). Here the authors show that translesion and replicative DNA polymerases cooperate via the POLD3 subunit to complete MiDAS in human cells.
- Wei Wu
- , Szymon A. Barwacz
- & Ying Liu
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Article
| Open AccessEfficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer
Immune checkpoint inhibitors with or without chemotherapy are now standard of care for non-small cell lung cancer. However, the benefits of combination vs sequential therapy have not been fully explored. Here, the authors analysed 1,133 patient records and show combination therapy showed increased protection against early progression, but similar overall survival.
- Lingzhi Hong
- , Muhammad Aminu
- & Natalie I. Vokes
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Article
| Open AccessAntitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers
In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.
- James J. Harding
- , Sarina A. Piha-Paul
- & Ghassan K. Abou-Alfa
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Article
| Open AccessEstablishment and validation of a plasma oncofetal chondroitin sulfated proteoglycan for pan-cancer detection
Developing multi-cancer early detection (MCED) tests based on cfDNA or protein markers holds great promise for effective cancer screening. Here, the authors show a sensitive, non-invasive pan-cancer detection method that concurrently detects the oncofetal chondroitin sulfate (ofCS) glycans and its protein backbone in plasma.
- Pei-Fen Zhang
- , Zi-Yi Wu
- & Wei-Hua Jia
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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