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| Open AccessAmyloid formation and depolymerization of tumor suppressor p16INK4a are regulated by a thiol-dependent redox mechanism
The conversion of a soluble protein into polymeric amyloid structures is poorly understood. Here the authors report that the tumor suppressor protein p16INK4a changes its structure upon oxidation to form aggregated amyloid fibrils, which are fully reversible upon disulfide bond reduction.
- Sarah G. Heath
- , Shelby G. Gray
- & Christoph Göbl
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Article
| Open AccessDelayed tumor-draining lymph node irradiation preserves the efficacy of combined radiotherapy and immune checkpoint blockade in models of metastatic disease
Despite the described immunostimulatory properties of irradiation, the clinical benefit of radiotherapy-immunotherapy combinations has been modest so far. Here, in murine models of metastatic disease, the authors show that concomitant draining lymph node irradiation (DLN IR) abrogates the beneficial effect of combining radiotherapy with immune checkpoint inhibitors, while adjuvant DLN IR improves regional and distant disease control.
- Irma Telarovic
- , Carmen S. M. Yong
- & Martin Pruschy
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Article
| Open AccessCRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer
Chemoresistance limits the success of chemotherapy in patients with cancer. Here, the authors perform 30 genome wide CRISPR knockout screens to identify genes associated to resistance against commonly used chemotherapeutics across multiple cancer types, followed by 26 second round CRISPR screens to identify druggable targets of chemoresistance.
- Chunge Zhong
- , Wen-Jie Jiang
- & Teng Fei
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Article
| Open AccessPIKfyve, expressed by CD11c-positive cells, controls tumor immunity
Myeloid cell subsets are playing important roles in antitumour immunity, and genes affecting their functions are potential targets for immunotherapy. Here authors show that genomic deletion of Pikfyve in CD11c+ cells results in tumour growth inhibition via enhanced antigen presentation and priming of antigen-specific CD8+ T cells in a mouse tumor model.
- Jae Eun Choi
- , Yuanyuan Qiao
- & Arul M. Chinnaiyan
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Article
| Open AccessExpression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response
Oncolytic viruses create an inflamed tumour microenvironment allowing T cells to respond to immune checkpoint blockade therapy more efficiently. Authors here show that in a hepatocellular carcinoma model, a dominant anti-viral rather than anti-tumour T cell response is elicited by an oncolytic vesicular stomatitis virus, unless the virus is designed to express tumour antigens, which restores therapeutic benefit.
- Mason J. Webb
- , Thanich Sangsuwannukul
- & Richard Vile
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Article
| Open AccessFarnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies
Emergence of drug tolerant cells drives adaptive targeted therapy resistance in non-small cell lung cancer (NSCLC). Here, the authors identify a common molecular event underpinning resistance to multiple targeted therapies in a panel of mutant NSCLC models that can be targeted with farnesyltransferase inhibition.
- Sarah Figarol
- , Célia Delahaye
- & Olivier Calvayrac
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Article
| Open AccessAI-based histopathology image analysis reveals a distinct subset of endometrial cancers
Endometrial cancer (EC) has four molecular subtypes; of these, the No Specific Molecular Profile (NSMP) subtype encompasses patients with heterogeneous outcomes. Here, the authors use artificial intelligence and histopathology images to differentiate p53abn and NSMP subtypes in EC, and identify one distinct subgroup within NSMP with unfavourable outcome.
- Amirali Darbandsari
- , Hossein Farahani
- & Ali Bashashati
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Article
| Open AccessMRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling
Oncogene-induced senescence is a key tumor suppressor mechanism. Here, the authors show that replication stress induced by the RASV12 oncogene activates the cGAS-STING pathway, which in turn acts as a positive feedback loop to promote senescence.
- Hervé Técher
- , Diyavarshini Gopaul
- & Yea-Lih Lin
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Article
| Open AccessDeep representation learning of chemical-induced transcriptional profile for phenotype-based drug discovery
While chemical-induced transcriptional profiles reveal drug mechanisms, inherent noise limits their utility. Here, authors present TranSiGen, a deep representation learning model that denoises and reconstructs these profiles, demonstrating its efficacy in downstream drug discovery tasks.
- Xiaochu Tong
- , Ning Qu
- & Mingyue Zheng
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Article
| Open AccessCancer cell plasticity defines response to immunotherapy in cutaneous squamous cell carcinoma
Immune surveillance is critical to prevent the development and progression of cutaneous squamous cell carcinoma (cSCC). Here, the authors show that epithelial-mesenchymal plasticity in cancer cells is associated with changes in their immune checkpoint ligand profile during mouse cSCC progression, which dictates differential responses to immune checkpoint blockade.
- Laura Lorenzo-Sanz
- , Marta Lopez-Cerda
- & Purificación Muñoz
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Article
| Open AccessCo-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma
Due to limited therapeutic options, patients with Ewing sarcoma typically receive intensive chemotherapy which limits quality of life and often resistance develops. Here, the authors identify a chemotherapy-induced JAK-STAT-GAS6-TAM kinase signaling cascade in Ewing sarcoma and therapeutically target this axis with TAM kinase inhibition.
- Le Yu
- , Yu Deng
- & Pengda Liu
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Article
| Open AccessPJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma
While chemotherapy may initially be effective in patient with nasopharyngeal carcinoma (NPC), resistance often develops. Here, the authors identify PJA1 as a driver of resistance to docetaxel via inhibition of GSDME-mediated proptosis and target this using a PJA1 inhibitor to restore sensitivity in preclinical models of NPC.
- Sheng-Yan Huang
- , Sha Gong
- & Na Liu
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Article
| Open AccessATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma
New strategies are needed to address treatment resistance in glioblastoma. Here the authors show that TP53-mutant glioblastomas rely upon ATM-dependent double strand break repair to resist DNA-damaging therapy, rendering them vulnerable to drug combinations employing ATM inhibitors.
- Daniel J. Laverty
- , Shiv K. Gupta
- & Zachary D. Nagel
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Article
| Open AccessIn vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer
Functional characterization of genetic alterations is a prerequisite for pancreatic cancer precision medicine. Here, using in vivo CRISPR screens, the authors integrate human cancer genomics and mouse models, identifying that loss of USP15 or SCAF1 accelerates tumor development and leads to reduced inflammatory responses and increased sensitivity to PARP inhibition and Gemcitabine.
- Sebastien Martinez
- , Shifei Wu
- & Daniel Schramek
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Article
| Open AccessSingle-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide
The hematopoiesis of patients with del(5q) Myelodysplastic Syndromes is composed of a mixture of cells with and without the deletion. Here, the authors show that del(5q) and non-del(5q) cells share similar transcriptional alterations, with del(5q) cells presenting additional lesions. Moreover, hematological response to lenalidomide is associated with the reversal of some transcriptional lesions in both del(5q) and non-del(5q) cells.
- Guillermo Serrano
- , Nerea Berastegui
- & Mikel Hernaez
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Article
| Open AccessCamrelizumab-based induction chemoimmunotherapy in locally advanced stage hypopharyngeal carcinoma: phase II clinical trial
Locally advanced hypopharyngeal squamous cell carcinoma is an aggressive form of head and neck cancer with a poor prognosis. Here, the authors report the safety and efficacy of induction camrelizumab (anti-PD-1) and chemotherapy for the treatment of locally advanced hypopharyngeal squamous cell carcinoma.
- Hongli Gong
- , Shu Tian
- & Liang Zhou
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Article
| Open AccessEffectiveness of COVID-19 vaccines against severe COVID-19 among patients with cancer in Catalonia, Spain
Observational studies are needed to understand the effectiveness of COVID-19 vaccines in groups not included in randomised controlled trials, such as patients with cancer. Here, the authors estimate effectiveness of COVID-19 primary and booster vaccine doses in individuals in Catalonia, Spain using primary care data.
- Felippe Lazar Neto
- , Núria Mercadé-Besora
- & Talita Duarte-Salles
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Article
| Open AccessMaster corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2
CtBP is a transcriptional master co-repressor with oncogenic activity. Here, the authors use structural and biophysical methods to show that CtBP interacts with RAI2 through SLiMs that induce CtBP polymerization and inactivation.
- Nishit Goradia
- , Stefan Werner
- & Matthias Wilmanns
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Article
| Open AccessThe binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer
GPRC5D is an atypical Class C orphan GPCR and an attractive target for therapeutic interventions. Here, the authors present the cryo-EM structure of the human GPRC5D and scFv complex, and elucidate the precise antibody binding mode and recpetor dimerization interface.
- Pengfei Yan
- , Xi Lin
- & Fei Xu
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Article
| Open AccessTherapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells
Ovarian cancers frequently develop resistance to therapy. Here, using transcriptomics, proteomics, and preclinical models to analyse paired ascitic fluids before and after chemotherapy in ovarian cancer patients, the authors discover that extracellular secretion and spliceosomal components contribute to therapy resistance, enhancing the DNA damage response in recipient cancer cells.
- Victoria O. Shender
- , Ksenia S. Anufrieva
- & Vadim M. Govorun
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Article
| Open AccessSiglec-6 as a therapeutic target for cell migration and adhesion in chronic lymphocytic leukemia
Siglec-6 is often overexpressed in chronic lymphocytic leukaemia (CLL), but its role is unclear. Here, the author report that Siglec-6 regulates the migration and adhesion of CLL B cells via interaction with sialyl Tn on bone marrow stromal cells driving invasion which could be therapeutically targeted using a Siglec-6/CD3-bispecfiic antibody.
- Jessica Nunes
- , Rakeb Tafesse
- & Natarajan Muthusamy
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Article
| Open AccessCholesterol efflux from C1QB-expressing macrophages is associated with resistance to chimeric antigen receptor T cell therapy in primary refractory diffuse large B cell lymphoma
Although the efficacy of chimaeric antigen receptor (CAR) T cell therapy has been demonstrated in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), it has not been investigated in primary refractory DLBCL. In this phase I clinical trial, the authors report on the safety and efficacy of relmacabtagene autoleucel, a CD19-specific CAR T cell product, and demonstrate using single-cell RNA sequencing that cholesterol efflux from macrophages may impair CAR T cell responses in this context.
- Zi-Xun Yan
- , Yan Dong
- & Wei-Li Zhao
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Article
| Open AccessHigh resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer
Here, the authors developed a method to precisely measure bulk, chromosome arm- and allele-specific human telomere length using nanopore sequencing. They resolve telomere shortening and differences between telomerase- and ALT-positive cancer cells
- Tobias T. Schmidt
- , Carly Tyer
- & Jan Karlseder
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Article
| Open AccessAcetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors
The relevance of spliceosome core components in cancer is less understood. Here the authors show SmD2, a core component of the spliceosome machinery, is under acetylation-dependent regulation, which could be targeted to enhance sensitivity to PARP inhibitors in hepatocellular carcinoma.
- Linmao Sun
- , Yufeng Liu
- & Lianxin Liu
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Article
| Open AccessCancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation
Missense mutations in histones can drive oncogenesis and disrupt chromatin, but the associated mechanisms for many such mutations remain poorly understood. Here, the authors show that cancer-associated histone mutations at arginines in the H3 N-terminal tail disrupt repressive chromatin domains, alter gene expression, and in one case impair differentiation via reduction of PRC2 function.
- Benjamin A. Nacev
- , Yakshi Dabas
- & C. David Allis
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Article
| Open AccessC-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer
Cancer stem cells (CSCs) have important roles in tumour initiation, metastasis and treatment resistance. Here, the authors show that C-terminally phosphorylated p27, together with STAT3, mediates the transcriptional regulation of CSC expansion, increasing cancer formation and metastasis in preclinical breast cancer models.
- Seyedeh Fatemeh Razavipour
- , Hyunho Yoon
- & Joyce M. Slingerland
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Article
| Open AccessHER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial
Safety concerns limit the success of HER2-targeting antibody-drug conjugates (ADCs) for the treatment of HER2-postive breast cancer. Here, the authors present a phase 1a/b trial reporting the safety and preliminary efficacy of FS-1502, an anti-HER2 ADC with a cancer-selective cleavable linker, for the treatment of HER2-positive metastatic breast cancer.
- Qiao Li
- , Ying Cheng
- & Binghe Xu
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Article
| Open AccessProgressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer
Aging-related cancer incidence remains not fully understood. Here, the authors depict a progressive process of senescence in murine mammary stem cells at single-cell resolution, which is governed by the transcription factor Bcl11b and associated with enhanced chemical-induced tumorigenesis in aged mice.
- Huiru Bai
- , Xiaoqin Liu
- & Shang Cai
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Article
| Open AccessNCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance
The NADPH oxidase 2 (NOX2) complex is a main reactive oxygen species (ROS) source during inflammation. Here the authors report that NCF4, a subunit of the NOX2 complex, acts a sensor of ROS levels and regulates NLRP3 and AIM2 inflammasome activation, associated with attenuated colorectal cancer progression.
- Longjun Li
- , Rudi Mao
- & Xiaopeng Qi
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Article
| Open AccessHyperbaric oxygen enhances tumor penetration and accumulation of engineered bacteria for synergistic photothermal immunotherapy
Delivering bacteria-based drug for cancer therapy is limited by their penetration into extracellular matrix (ECM). Here the authors report effective depletion of ECM with hyperbaric oxygen therapeutic strategy to enhance bacterial accumulation within tumors and to induce immunogenic cell death.
- Ke-Fei Xu
- , Shun-Yu Wu
- & Fu-Gen Wu
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Article
| Open AccessDeep cell phenotyping and spatial analysis of multiplexed imaging with TRACERx-PHLEX
Imaging dozens of proteins in situ and at large scales increases the complexity of data analysis. Here, the authors develop an end-to-end solution for multiplexed image analysis that facilitates data interpretation for clinically relevant insights.
- Alastair Magness
- , Emma Colliver
- & Mihaela Angelova
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Article
| Open AccessChip collection of hepatocellular carcinoma based on O2 heterogeneity from patient tissue
Hepatocellular carcinoma is the most common type of primary liver cancer. Here the authors show an oxygen gradient chip that separates aggressive hepatocellular carcinoma cells from a heterogeneous tumor mass, mirroring the conditions of the portal vein, hepatic artery, and liver.
- Sewoom Baek
- , Hyun-Su Ha
- & Hak-Joon Sung
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Article
| Open AccessMechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers
Tyrosine kinases are promising therapeutic targets in multiple cancer types; however, the formation and selection of tyrosine kinase fusions are not fully understood. Here, the authors develop a genome-wide fusion sequencing platform and identify mechanisms and patterns of fusion formation that have implication for targeted therapy.
- Taek-Chin Cheong
- , Ahram Jang
- & Roberto Chiarle
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Article
| Open AccessGenomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident
Childhood radioactive iodine exposure from the Chornobyl accident led to an increased papillary thyroid carcinoma (PTC) risk and potentially higher invasiveness depending on tumour genetic profiles. Here, the authors use genomics to characterise and predict cervical lymph node metastases in PTC patients affected by the Chornobyl accident.
- Lindsay M. Morton
- , Olivia W. Lee
- & Stephen J. Chanock
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Article
| Open AccessProstate cancer reshapes the secreted and extracellular vesicle urinary proteomes
Urine can be used to easily analyse the health of patients. Here, the authors identify proteins in urinary extracellular vesicles that distinguish prostate cancer from benign lesions.
- Amanda Khoo
- , Meinusha Govindarajan
- & Thomas Kislinger
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Article
| Open AccessMixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling
Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.
- Sebastijan Hobor
- , Maise Al Bakir
- & Charles Swanton
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Article
| Open AccessDissecting tumor microenvironment from spatially resolved transcriptomics data by heterogeneous graph learning
Dissecting the relations between cells, genes, and histological regions in the tumor microenvironment (TME) remains challenging. Here, the authors develop stKeep, a heterogeneous graph learning method that integrates multimodal data and gene-gene interactions to identify cell states and composition in the TME from spatial transcriptomics.
- Chunman Zuo
- , Junjie Xia
- & Luonan Chen
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Article
| Open AccessProgrammable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies
The efficacy of cancer radio-immunotherapy is limited by the immunosuppressive tumor microenvironment. Here the authors report fusogenic liposomes loaded with Auranofin, a gold containing drug approved for rheumatoid arthritis, multivariate-gated aptamer assemblies and PD-L1 aptamers, as an adjuvant for melanoma-targeted radio-immunotherapy.
- Xijiao Ren
- , Rui Xue
- & Fudi Wang
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Article
| Open AccessCoHIT: a one-pot ultrasensitive ERA-CRISPR system for detecting multiple same-site indels
Genetic testing is crucial for precision cancer medicine. Here, the authors develop a one-pot ERA-CRISPR assay to detect variable same-site indels, using an engineered AsCas12a variant with improved mismatch tolerance and broadened PAM scope.
- Yin Liu
- , Xinyi Liu
- & Fuling Zhou
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Article
| Open AccessdescSPIM: an affordable and easy-to-build light-sheet microscope optimized for tissue clearing techniques
Poor access to suitable light-sheet microscopes remains a big obstacle for many end-users in biomedical research. Here, the authors present descSPIM, a low-cost, low-expertise light-sheet microscope for routine 3D imaging of cleared samples.
- Kohei Otomo
- , Takaki Omura
- & Etsuo A. Susaki
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Article
| Open AccessMYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration
The molecular mechanisms underlying metabolic remodelling in colorectal cancer (CRC) are not completely elucidated. Here, they authors show that the oncogenic protein MYG1 promotes CRC progression not only through regulating mitochondrial activity, but also through activating a nuclear-associated pathway for glycolysis increase.
- Jianxiong Chen
- , Shiyu Duan
- & Jun Zhou
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Article
| Open AccessThe RNF214-TEAD-YAP signaling axis promotes hepatocellular carcinoma progression via TEAD ubiquitylation
RNF214 ubiquitin ligase is understudied. Here the authors show RNF214 promotes hepatocellular carcinoma progression by inducing non-proteolytic ubiquitylation of TEADs and activating YAP signaling pathway.
- Mengjia Lin
- , Xiaoyun Zheng
- & Jianping Jin
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Article
| Open AccessMapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides
Supervised deep learning models hold promise for the interpretation of histology images, but are limited by cost and quality of training datasets. Here, the authors develop a self-supervised deep learning method that can automatically discover features in cancer histology images that are associated with diagnosis, survival, and molecular phenotypes.
- Adalberto Claudio Quiros
- , Nicolas Coudray
- & Ke Yuan
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Article
| Open AccessMolecular mechanism of BMP signal control by Twisted gastrulation
Twisted gastrulation (TWSG1) controls signaling by Bone Morphogenetic Proteins (BMPs) during embryogenesis and cancer. Here, author report crystal structures of TWSG1 in complex with a BMP ligand and show how TWSG1 inhibits signaling in cells and in vivo.
- Tomas Malinauskas
- , Gareth Moore
- & Christian Siebold
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Article
| Open AccessImmunological synapse formation between T regulatory cells and cancer-associated fibroblasts promotes tumour development
Cancer-associated fibroblasts (CAFs) are a predominant stromal cell population in the tumour microenvironment. Here, the authors demonstrate that αSMA + CAFs can form an immunological synapse with regulatory T cells (Tregs) in tumours, which results in Treg activation and expansion in a process that is antigen- and autophagy-dependent.
- Athina Varveri
- , Miranta Papadopoulou
- & Panayotis Verginis
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Article
| Open AccessTobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression
Tobacco smoking is an important risk factor for lung cancer. Here the authors report that tobacco carcinogens promote metabolic syndrome and metabolic reprogramming of macrophages, associated with lung cancer progression in preclinical models.
- Hyun-Ji Jang
- , Hye-Young Min
- & Ho-Young Lee
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Article
| Open AccessFOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer
The role of the FOXA1 to FOXA2 switch in the regulation of the response to androgen receptor signalling inhibition and lineage plasticity in prostate cancer remains unclear. Here, the authors highlight the function of FOXA2 in rewiring AP-1 to induce differential transcriptional reprogramming and lineage plasticity.
- Zifeng Wang
- , Scott L. Townley
- & Changmeng Cai
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Article
| Open AccessGermline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries
The role of ancestry in target discovery remains to be systematically explored. Here, the authors analyse data from 611 genome scale CRISPR/Cas9 viability experiments in human cell line models as part of The Cancer Dependency Map and identify ancestry-associated genetic dependencies.
- Sean A. Misek
- , Aaron Fultineer
- & Jesse S. Boehm
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Article
| Open AccessA YAP-centered mechanotransduction loop drives collective breast cancer cell invasion
Aligned collagen I is associated with the emergence of leader cells that are responsible for collective invasion. Here, the authors show that Collagen I and Yap signalling are in a feed-forward loop to drive the collective invasion of basal-like tumour cells.
- Antoine A. Khalil
- , Daan Smits
- & Johan de Rooij
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