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Cancer-associated fibroblast subtypes modulate the tumor-immune microenvironment and are associated with skin cancer malignancy
Fibroblast heterogeneity in the tumor microenvironment can explain their multifaceted role in cancer. Here by single-cell transcriptomic analysis of basal cell carcinoma, squamous cell carcinoma and melanoma samples, the authors explore fibroblast heterogeneity in skin cancer and their potential to modulate the tumor-immune microenvironment.
- Agnes Forsthuber
- , Bertram Aschenbrenner
- & Beate M. Lichtenberger
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Article
| Open Access
PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia
Glucocorticoid resistance is partly due to epigenetic alterations, but the regulatory mechanisms driving these remain poorly understood. Here, a link between the activity of a lineage-specific transcription factor PU.1 and epigenetic modulators mediating the response to glucocorticoids is described in acute lymphoblastic leukemia.
- Dominik Beck
- , Honghui Cao
- & Duohui Jing
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Article
| Open Access
Non-secreting IL12 expressing oncolytic adenovirus Ad-TD-nsIL12 in recurrent high-grade glioma: a phase I trial
Oncolytic viruses have been tested in patients with malignant glioma, however clinical efficacy remains limited. Here the authors report the results of a phase I trial of Ad-TD-nsIL12, an oncolytic adenovirus expressing a mutant (non-secreting) form of IL12, in patients with high-grade glioma.
- Weihai Ning
- , Xiao Qian
- & Hongwei Zhang
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Article
| Open Access
An explainable longitudinal multi-modal fusion model for predicting neoadjuvant therapy response in women with breast cancer
Deep learning for medical image analysis is a promising new avenue to predict treatment response, however the clinical application of these methods has been so far limited. Here, the authors propose a model to predict chemotherapy response in breast cancer in real world clinical settings.
- Yuan Gao
- , Sofia Ventura-Diaz
- & Ritse Mann
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Article
| Open Access
Neuroblastoma plasticity during metastatic progression stems from the dynamics of an early sympathetic transcriptomic trajectory
The roots of neuroblastoma plasticity and heterogeneity remain poorly understood. Here, the authors characterise the transcriptional states of neuroblastoma cells and their changes throughout development using avian embryo models, single-cell RNA-sequencing, and patient samples; they find transcriptomic changes related to early sympatho-adrenal development.
- Benjamin Villalard
- , Arjan Boltjes
- & Valérie Castellani
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Article
| Open Access
A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer
The PSA (KLK3) genetic variant rs17632542 is associated with reduced prostate cancer risk and lower serum PSA levels, although the underlying reasons are unclear. Here, the authors show that this PSA variant reduced proteolytic activity and leads to smaller tumours, but also increases invasion and bone metastasis, indicating its dual risk association depending on tumour context; the variant is associated with both lower risk and poor clinical outcomes.
- Srilakshmi Srinivasan
- , Thomas Kryza
- & Jyotsna Batra
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Efficacy and safety of JMT103 in patients with unresectable or surgically-challenging giant cell tumor of bone: a multicenter, phase Ib/II study
Giant cell tumor of bone (GCTB) is a rare primary osteolytic bone tumor with high local recurrence rate after surgical resection. Here the authors conduct a phase Ib/II trial, evaluating the efficacy and safety of JMT103 (RANK-RANKL inhibitor) in patients with unresectable or surgically-challenging GCTB.
- Hairong Xu
- , Yong Zhou
- & Xiaohui Niu
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Article
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Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer
While CDK4/6 inhibitors (CDK4/6i) have improved outcomes for breast cancer patients, estrogen receptor (ER + ) breast cancers often develop resistance, and triple negative breast cancer (TNBC) show poor sensitivity. Here, the authors identify a vulnerability of CDK4/6i treated ER+ and TNBC on ferroptosis and identify the combination of CDK4/6i and GPX4 inhibition as synergistic.
- M. T. Herrera-Abreu
- , J. Guan
- & N. C. Turner
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Article
| Open Access
A bispecific CD40 agonistic antibody allowing for antibody-peptide conjugate formation to enable cancer-specific peptide delivery, resulting in improved T proliferation and anti-tumor immunity in mice
Current applications of CD40-directed cancer immunotherapy rely on the release of endogenous tumor antigen for T cell priming and activation. Here the authors develop a bispecific CD40 agonistic antibody for modular delivery of antigenic peptides combined with CD40 stimulation and find that this improves T cell expansion and anti-tumor response in mice.’
- Aman Mebrahtu
- , Ida Laurén
- & Sara Mangsbo
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Article
| Open Access
PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity
PTPRK is a key protein in the transformation of normal to tumorigenic liver cells in obesity, providing fuel and lipids. Here, the authors show that genetic deletion of PTPRK in mice protects against fatty liver in an obesogenic diet and the development of liver cancer.
- Eduardo H. Gilglioni
- , Ao Li
- & Esteban N. Gurzov
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Article
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Genomic and transcriptomic landscape of human gastrointestinal stromal tumors
Gastrointestinal stromal tumours (GISTs) are clinically heterogeneous, with varying degrees of aggressiveness. Here, the authors describe the genomic and transcriptomic landscape of 117 GISTs from 105 patients; they find four molecular subtypes as well as recurrent inactivating YLPM1 mutations in high-risk/metastatic GIST.
- Feifei Xie
- , Shuzhen Luo
- & Yuexiang Wang
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Article
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Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance
The EML4-ALK oncogene forms cytoplasmic protein condensates that are associated with its oncogenic signaling. Here, the authors demonstrate that these EML4-ALK assemblies also sequester receptor tyrosine kinase (RTK) adapter proteins suppressing signaling which was reversed upon ALK inhibition, resulting in rapid resensitisation to growth factors and tumor cell survival.
- David Gonzalez-Martinez
- , Lee Roth
- & Lukasz J. Bugaj
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Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells
Mechanisms of prostaglandin E2 (PGE2)-mediated immunosuppression in the tumor microenvironment (TME) have been previously reported. Here, the authors profile PGE2 functions in human cancer, suggesting that prostaglandin E2-mediated signaling impairs the activity of human CD8+ T cells and macrophages by altering bioenergetics and ribosome biogenesis.
- Siwakorn Punyawatthananukool
- , Ryuma Matsuura
- & Shuh Narumiya
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Article
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Tumor-targeted glutathione oxidation catalysis with ruthenium nanoreactors against hypoxic osteosarcoma
Hypoxic tumor microenvironment (TME) limits the therapeutic efficacy of anticancer drugs. Here this group reports a ruthenium-based nanocatalyst alleviating hypoxic TME, activating protein transient receptor potential melastatin 2 ion channel, promoting systemic immune response thereby eliciting its therapeutic efficacy against osteosarcoma.
- Hanchen Zhang
- , Nicolás Montesdeoca
- & Johannes Karges
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Article
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Self-assembled aldehyde dehydrogenase-activatable nano-prodrug for cancer stem cell-enriched tumor detection and treatment
Cancer stem cells (CSC) are often responsible for tumor progression and metastasis and can overexpress aldehyde dehydrogenases (ALDHs). Here, the authors develop a self-assembled nanoprodrug (PS-CHO@ATRA-SS-ATRA) composed of ALDH-activatable photosensitizer (PS-CHO) and disulfide-linked all-trans retinoic acid (ATRA-SS-ATRA) for diagnosis and targeted treatment of CSC-enriched tumors.
- Bowen Li
- , Jianwu Tian
- & Bin Liu
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Article
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HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells
Anti-cancer immunity relies on the effector functions (e.g., IFNγ production) of T cells that reside in a hypoxic tumor microenvironment. Here, the authors show that HIF1α-controlled glycolysis is an important driver of IFNγ production in hypoxic T cells, governing anti-tumor immunity.
- Hongxing Shen
- , Oluwagbemiga A. Ojo
- & Lewis Zhichang Shi
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Spatial proteomics of single cells and organelles on tissue slides using filter-aided expansion proteomics
Hydrogel-based tissue expansion proteomics represents an emerging spatial proteomics approach. Here, the authors develop the filter-aided expansion proteomics (FAXP) strategy, enabling proteomic analysis of single cells and nuclei in formalin-fixed paraffin-embedded (FFPE) tissue sections.
- Zhen Dong
- , Wenhao Jiang
- & Tiannan Guo
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Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia
The molecular mechanisms underlying drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML) remain to be explored. Here, the use of bulk and single cell multi-omics and ex vivo drug profiling for 21 rrAML patients reveals mechanisms of resistance to the Bcl-2 inhibitor venetoclax and treatment vulnerabilities.
- Rebekka Wegmann
- , Ximena Bonilla
- & Alexandre P. A. Theocharides
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Article
| Open Access
MLL oncoprotein levels influence leukemia lineage identities
The effects of chromosomal translocations involving the mixed-lineage leukemia (MLL) locus on gene expression regulation remain to be explored. Here, the authors find that MLL oncoproteins support lineage-switching events through dynamic chromatin binding.
- Derek H. Janssens
- , Melodie Duran
- & Steven Henikoff
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Article
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Supercontinuum-tailoring multicolor imaging reveals spatiotemporal dynamics of heterogeneous tumor evolution
Studying tumour heterogeneity and tumour evolution remains a challenging task. Here, the authors propose a supercontinuum-tailoring two-photon microscope to enable the imaging of multiple fluorophores with a single light beam. They use this tool to monitor the dynamics of heterogeneous tumour evolution.
- Xiujuan Gao
- , Xinyuan Huang
- & Ling Fu
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Article
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Perioperative Tislelizumab plus intensity modulated radiotherapy in resectable hepatocellular carcinoma with macrovascular invasion: a phase II trial
Macrovascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) is associated with poor prognosis and limited therapeutic options. Here the authors report the results of a phase 2 trial of perioperative tislelizumab (anti-PD1) plus intensity modulated radiotherapy in resectable HCC with MVI.
- Hongyu Pan
- , Liuyu Zhou
- & Ruoyu Wang
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Article
| Open Access
Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells
In liver metastasis of cancer, the inflammatory macrophage niche is dominated by both circulating monocytes and local expansion, but the nature and dynamic of this niche is still unclear. Here the authors use mouse genetic models and lineage-tracing tools to show that, under the condition of monocyte depletion, Kupffer cells pursue epigenetic reprogramming to contribute to this niche.
- Han-Ying Huang
- , Yan-Zhou Chen
- & Lin Tian
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Article
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Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways
Here the authors suggest that in Atypical Teratoid Rhabdoid Tumors, EZH2 inhibition triggers a viral mimicry response via the activation of genes with intronic IR-Alu elements. This response also involves enhanced LINE-1 expression, leading to activation of cGAS/STING signalling.
- Shengrui Feng
- , Sajid A. Marhon
- & Daniel D. De Carvalho
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Article
| Open Access
Integrative spatial and genomic analysis of tumor heterogeneity with Tumoroscope
In this article the authors develop “Tumoroscope" to map cancer clones by integrating pathology images, exome sequencing, and spatial transcriptomics. It reveals spatial clone patterns and clone-specific gene expression in prostate and breast cancer, advancing tumor heterogeneity analysis.
- Shadi Shafighi
- , Agnieszka Geras
- & Ewa Szczurek
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Article
| Open Access
Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors
The molecular mechanisms underlying the late-onset adverse effects of radiotherapy remain to be explored. Here, the authors observe compromised wound healing capacity in irradiated skin from breast cancer survivors and highlight THBS1 as a key epigenetically primed wound repair-related gene.
- Xiaowei Bian
- , Minna Piipponen
- & Ning Xu Landén
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Article
| Open Access
Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project
Testicular germ cell tumours (TGCT) are the most common cancers in young men. Here, the authors analyse the genomic landscape of TGCT using data from the Genomics England 100,000 Genomes Project, revealing divergent evolutionary trajectories and the prevalence of human leukocyte antigen loss.
- Máire Ní Leathlobhair
- , Anna Frangou
- & Clare Verrill
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Article
| Open Access
Suppressive cancer nonstop extension mutations increase C-terminal hydrophobicity and disrupt evolutionarily conserved amino acid patterns
Nonstop extension mutations in cancer remain poorly characterized. Here, the authors test the impact of 2335 tumor-derived C-terminal nonstop extensions on protein expression and find the majority to be suppressive; they also analyze their biochemical properties and relation to evolutionary selection patterns.
- Avantika Ghosh
- , Marisa Riester
- & Sven Diederichs
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Article
| Open Access
Comparative analysis of methodologies for detecting extrachromosomal circular DNA
Sequencing-based studies have advanced our understanding of the diverse functions of extrachromosomal circular DNA (eccDNA). Here the authors systematically compare the performance of several bioinformatic pipelines and experimental methods that have been developed for eccDNA detection.
- Xuyuan Gao
- , Ke Liu
- & Kun Qu
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Article
| Open Access
Osteopontin is a therapeutic target that drives breast cancer recurrence
Osteopontin promotes tumor growth in several cancer types. Here, in a preclinical model recapitulating features of human breast cancer recurrence, the authors report that osteopontin promotes the recruitment of immunosuppressive macrophages and its targeting reduces breast tumor growth and metastasis.
- Yu Gu
- , Tarek Taifour
- & William J. Muller
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Article
| Open Access
Chemotherapy resistance in acute myeloid leukemia is mediated by A20 suppression of spontaneous necroptosis
Patients with Acute myeloid leukemia (AML) who do not respond to standard chemotherapy have limited treatment options. Here, the authors show that high expression of the gene TNFAIP3/A20 in AML cells contributes to chemotherapy resistance by blocking a type of cell death called necroptosis.
- Ashley E. Culver-Cochran
- , Aishlin Hassan
- & Daniel T. Starczynowski
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Article
| Open Access
LLM-driven multimodal target volume contouring in radiation oncology
The integration of multimodal knowledge would be essential for radiation oncologist to determine the therapeutic treatment. Here, inspired by the large language models facilitating the integration of textural information and images, this group reports a 3D multimodal clinical target volume delineation model combining image and text-based clinical information for decision-making in radiation oncology.
- Yujin Oh
- , Sangjoon Park
- & Jong Chul Ye
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Article
| Open Access
A splicing isoform of PD-1 promotes tumor progression as a potential immune checkpoint
Whether PD-1 splicing isoforms impact T cell anti-tumor capacity has not been fully illustrated. Here the authors identify a human PD-1 isoform, PD-1^28, which functions to suppress anti-cancer immunity in vitro and in both syngeneic and humanized mouse tumor models.
- Xuetong Wang
- , Tongfeng Liu
- & Shan Gao
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Article
| Open Access
Single-cell sequencing reveals immune features of treatment response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma
The tumour microenvironment features influencing response to neoadjuvant immunochemotherapy (nICT) in esophageal squamous cell carcinoma (ESCC) remain to be explored. Here, single cell and TCR sequencing on pre- and post- nICT treatment ESCC tissues identifies the presence of CXCL13+CD8+ T cells as a predictor of improved response and the enrichment of TNFRSF4+CD4+ Tregs as a marker of treatment resistance.
- Zhenlin Yang
- , He Tian
- & Shugeng Gao
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Article
| Open Access
Oral reovirus reshapes the gut microbiome and enhances antitumor immunity in colon cancer
Here, the authors show that oral administration of an oncolytic reovirus (RC402) elicits robust suppression of multifocal tumor lesions and antitumor immunity through extensive rewiring of the host immunity and the gut microbiome.
- Won Suk Lee
- , Seung Joon Lee
- & Chan Kim
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Article
| Open Access
Modeling NK-cell lymphoma in mice reveals its cell-of-origin and microenvironmental changes and identifies therapeutic targets
Extranodal NK/T-cell lymphoma (ENKTCL) is an aggressive Epstein-Barr virus (EBV)-related neoplasm. Here the authors report a genetically engineered mouse model harboring NK-cellspecific Trp53 deletion to model ENKTCL in mice
- Junji Koya
- , Tomohiko Tanigawa
- & Keisuke Kataoka
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Article
| Open Access
Peptidylprolyl isomerase A guides SENP5/GAU1 DNA-lncRNA triplex generation for driving tumorigenesis
This study investigates the regulatory mechanisms of DNA-lncRNA triplexes, specifically their role in gastric cancer through the stable formation and precise oncogenic activity of the SENP5/GAU1 triplex. It shows how PPIA orchestrates the SENP5/GAU1 DNA-lncRNA triplex.
- Xiaoyu Zhang
- , Tianyi Ding
- & He Zhang
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Article
| Open Access
Cancer treatment monitoring using cell-free DNA fragmentomes
Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically use tumor-specific mutations that may not be detected in many patients. Here, the authors develop a tumor-independent and mutation-independent approach (DELFI-TF) to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction.
- Iris van ’t Erve
- , Bahar Alipanahi
- & Alessandro Leal
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Article
| Open Access
Hallmarks of a genomically distinct subclass of head and neck cancer
HPV-negative head and neck squamous cell carcinomas (HNSCCs) are generally characterized by many copy number alterations (CNAs) and mutations. Here, the authors characterize a subgroup of HPV-negative HNSCC with no or few CNAs (CNA-quiet) by genomic profiling of 802 oral cavity squamous cell carcinomas.
- Tara Muijlwijk
- , Irene H. Nauta
- & Ruud H. Brakenhoff
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Article
| Open Access
Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer
Prostate cancers (PCa) are characterized by an immunosuppressive tumor microenvironment. Here the authors identify a subset of iron-loaded cancer-associated fibroblasts secreting myeloid cell-associated proteins and driving immunosuppression in PCa.
- Kai Zhang
- , Kaiyuan Liu
- & Helen He Zhu
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Article
| Open Access
Benchmarking machine learning methods for synthetic lethality prediction in cancer
A comprehensive benchmarking of existing synthetic lethality (SL) prediction methods is lacking. Here, the authors compare 12 recently developed machine learning methods for SL prediction, assess their performance, and provide guidance on the selection of the most suitable method.
- Yimiao Feng
- , Yahui Long
- & Jie Zheng
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Article
| Open Access
Spatial dynamics of CD39+CD8+ exhausted T cell reveal tertiary lymphoid structures-mediated response to PD-1 blockade in esophageal cancer
Immune checkpoint blockade (ICB) benefits esophageal squamous cell cancer, but the immune cell mediators remain unclear. Here the author show, by imaging mass cytometry, that CD39+CD8+ exhausted cells are present abundantly in both tertiary lymphoid tissue and tumor and correlate with responses to ICB.
- Kenro Tanoue
- , Hirofumi Ohmura
- & Eishi Baba
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Article
| Open Access
The integrated molecular and histological analysis defines subtypes of esophageal squamous cell carcinoma
The clinical outcomes of esophageal squamous cell carcinoma (ESCC) remain poor, and thus it remains critical to find prognostic molecular markers. Here, the authors identify prognostic ESCC subtypes based on bulk and single-cell RNA-seq combined with histology AI in samples from patients with more than four years of follow-up, and find markers associated with immune evasion.
- Guozhong Jiang
- , Zhizhong Wang
- & Yaohe Wang
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Article
| Open Access
Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma
Neuroblastoma (NB) is a frequent childhood cancer that often becomes resistant to therapy. Here, the authors perform spatiotemporal genomic profiling of NBs before and after chemotherapy and find an evolutionary process characteristic of NBs growing resistant after first responding to treatment.
- Jenny Karlsson
- , Hiroaki Yasui
- & David Gisselsson
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Article
| Open Access
Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma
Pediatric brain cancers are lethal malignancies driven by less-differentiated stem-like cells. Here the authors show that these cells exhibit distinct mitochondrial metabolism programs with targetable vulnerabilities.
- Nneka E. Mbah
- , Amy L. Myers
- & Costas A. Lyssiotis
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Article
| Open Access
Generalizable and automated classification of TNM stage from pathology reports with external validation
Cancer staging is an essential clinical attribute. However, it is not routinely recorded in electronic health records. Here, the authors present a generalizable method for the automated classification of TNM stage from pathology report text.
- Jenna Kefeli
- , Jacob Berkowitz
- & Nicholas P. Tatonetti
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Article
| Open Access
Nivolumab plus anlotinib hydrochloride in advanced gastric adenocarcinoma and esophageal squamous cell carcinoma: the phase II OASIS trial
Anlotinib hydrochloride is a multi-target tyrosine kinase receptor inhibitor, previously combined with anti-PD1 as therapeutic strategy for several cancer types. Here the authors report the results of a phase II trial of nivolumab (anti-PD1) plus anlotinib hydrochloride in patients with advanced gastric adenocarcinoma and esophageal squamous cell carcinoma.
- Jing Wu
- , Shilong Zhang
- & Yuehong Cui
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Article
| Open Access
Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer
The IRE1α-XBP1s pathway has been implicated in the regulation of anti-tumor immunity. Here the authors show that IRE1α is increased in prostate cancer (PCa) and that its inhibition reprograms the tumor microenvironment, promoting anti-tumor immune responses in PCa preclinical models.
- Bilal Unal
- , Omer Faruk Kuzu
- & Fahri Saatcioglu
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Article
| Open Access
Plasma proteomic and polygenic profiling improve risk stratification and personalized screening for colorectal cancer
Non-invasive approaches for risk stratification and screening remain crucial for colorectal cancer (CRC). Here, the authors develop a model for CRC risk stratification by integrating plasma proteomics data with polygenic risk score and QCancer-15 risk score, which could guide recommendations for earlier screening of high-risk populations.
- Jing Sun
- , Yue Liu
- & Xue Li
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Article
| Open Access
Prospective assessment of circulating tumor DNA in patients with metastatic uveal melanoma treated with tebentafusp
Response to tebentafusp is variable in patients with metastatic uveal melanoma. Here, the authors use droplet digital PCR to detect ctDNA and show that ctDNA positivity was associated with shorter overall survival.
- Manuel Rodrigues
- , Toulsie Ramtohul
- & Shufang Renault
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