Featured
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| Open AccessDecoding kinase-adverse event associations for small molecule kinase inhibitors
Small molecule kinase inhibitors (SMKIs) are being approved at a fast pace under expedited programs for anticancer treatment. Here, the authors employ a machine-learning model to examine the relationships between kinase targets and adverse events in the trials of 16 FDA-approved SMKIs.
- Xiajing Gong
- , Meng Hu
- & Liang Zhao
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Article
| Open AccessEngineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy
Proteolysis targeting chimeras (PROTACs) have emerged as promising cancer therapy agents but have suffered from systemic toxicity issues. Here, the authors report on the creation of polymeric PROTAC nanoparticles for tumour targeting delivery and demonstrate protein degradation in vivo, in combination with photodynamic therapy.
- Jing Gao
- , Bo Hou
- & Haijun Yu
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Article
| Open AccessPancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement
Pharmacological inhibition of the prolyl isomerase PIN1, highly expressed in cancer cells and cancer associated fibroblasts (CAF), has been proposed for cancer therapy. Here the authors report the design of a DNA-barcoded micellular system functionalized with antibodies targeting CAFs and a T cell recruiting aptamer to deliver the PIN1 inhibitor AG17724, showing antitumor response in preclinical models of pancreatic cancer.
- Jiaye Liu
- , Yang Wang
- & Yong Liu
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Article
| Open AccessIntratumor graph neural network recovers hidden prognostic value of multi-biomarker spatial heterogeneity
Cancer prognosis using multiregion sampling is costly and not completely reliable due to the required biomarker homogenisation step. Here, the authors develop an intratumor graph neural network for prognosis in multiregion cancer samples based on in situ biomarkers and gene expression that does not need homogenisation.
- Lida Qiu
- , Deyong Kang
- & Haohua Tu
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Article
| Open AccessEngineered biomimetic nanoparticles achieve targeted delivery and efficient metabolism-based synergistic therapy against glioblastoma
Targeting cancer-associated metabolism is evolving as a promising approach for cancer therapy. Here, the authors generate cancer cell-membrane encapsulated nanoparticles to induce cell cycle arrest and cytotoxicity in lactate-high cancer cells, reducing tumourigensis in glioblastoma cell-line and patient-derived models.
- Guihong Lu
- , Xiaojun Wang
- & Wei Wei
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Article
| Open AccessProteomic analysis reveals key differences between squamous cell carcinomas and adenocarcinomas across multiple tissues
Squamous cell carcinomas are an aggressive cancer type which can occur in multiple organ systems. Here, the authors analyse the proteome of SCC cancers from 17 organs and show commonly dysregulated proteins independent of location.
- Qi Song
- , Ye Yang
- & Yingyong Hou
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Article
| Open AccessHypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy
Hypoxia can promote tumor escape from immune surveillance and immunotherapy. Here, the authors show that hypoxia induces T and NK cell dysfunction through HIF1α-mediated epigenetic suppression of effector gene expression, conferring resistance to anti-PD1 blockade in triple negative breast cancer models.
- Shijun Ma
- , Yue Zhao
- & Qiang Yu
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Article
| Open AccessQualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer
MEK1 mutations are found in cancer and RASopathies, but their effects remain unclear. Here, the authors reveal a mutant MEK1 structure and qualitative differences in biological properties between the cancer- and RASopathy-associated mutants, providing insights into the pathophysiology, diagnosis, and treatment of these diseases.
- Yuji Kubota
- , Yuko Fujioka
- & Mutsuhiro Takekawa
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Article
| Open AccessIntegration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer
Some cancer patients with impaired HLA-I still respond to immunotherapy. Here the authors combine a cytotoxic gene signature from CD4+ and CD8+ T cells with tumor mutational burden to predict immunotherapy response in NSCLC patients, including those with HLA-LOH.
- Denise Lau
- , Sonal Khare
- & Aly A. Khan
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Article
| Open AccessThe HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors
Long non-coding RNAs (lncRNAs) can contribute to cancers that are driven by Sonic hedgehog (SHH) signaling. Here the authors report that lncRNA HHIP-AS1 stabilises the mRNA of dynein complex 1, thereby, promoting the pro-mitotic effects of SHH-driven tumors.
- Jasmin Bartl
- , Marco Zanini
- & Marc Remke
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Article
| Open AccessA randomized phase 3 trial of Gemcitabine or Nab-paclitaxel combined with cisPlatin as first-line treatment in patients with metastatic triple-negative breast cancer
Platinum agents, such as carboplatin and cisplatin, have been recommended in combination with gemcitabine for the treatment of metastatic triple negative breast cancer (TNBC). Here the authors report the results of a randomized phase 3 trial to compare the efficacy of first-line nab-paclitaxel/cisplatin to gemcitabine/cisplatin in patients with TNBC.
- Biyun Wang
- , Tao Sun
- & Xichun Hu
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Article
| Open AccessMulti-modal molecular programs regulate melanoma cell state
The regulation of the distinct intrinsic phenotypic states in melanoma remain poorly characterised. Here, multi-omics analysis for a panel of 68 early passage melanoma cell lines reveals that cancer cell intrinsic transcriptomic programs are associated with distinct immune features.
- Miles C. Andrews
- , Junna Oba
- & Scott E. Woodman
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Matters Arising
| Open AccessLimitations of molecular testing in combination with computerized tomographic for lung cancer screening
- Frederic W. Grannis Jr
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Article
| Open AccessThe cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
Looking for metabolic-associated vulnerabilities is a promising approach for therapeutic intervention in KRAS-mutant colorectal cancer. Here, the authors show that the cholesterol-uptake regulator PCSK9 drives tumourigenesis and is a therapeutic target in KRASmutant colorectal cancer.
- Chi Chun Wong
- , Jian-Lin Wu
- & Jun Yu
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Article
| Open AccessRecurrent somatic mutations as predictors of immunotherapy response
Few genetic biomarkers are known for cancer immunotherapy. Here the authors identify recurrently-mutated genes and pathways associated with treatment response and develop a classifier using tumour whole exome sequencing and clinical features.
- Zoran Z. Gajic
- , Aditya Deshpande
- & Neville E. Sanjana
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Article
| Open AccessClinical relevance of molecular characteristics in Burkitt lymphoma differs according to age
Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.
- Birgit Burkhardt
- , Ulf Michgehl
- & Georg Lenz
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Article
| Open AccessMonomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy
Monomethyl auristatin (MMAE), also known for its radiosensitizer properties, is a common antibody drug conjugate used for cancer therapy. Here the authors show that, in combination with radiotherapy, tumor-directed antibodies or peptides conjugated to MMAE promote anti-tumor immune responses, improving response to checkpoint inhibitors in preclinical cancer models.
- Dina V. Hingorani
- , Michael M. Allevato
- & Sunil J. Advani
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Article
| Open AccessAn in situ hydrogel-mediated chemo-immunometabolic cancer therapy
Tryptophan metabolism, leading to the accumulation of kynurenine (Kyn) in the tumor microenvironment, restricts anti-tumor immunity. Here the authors report the design of a hydrogel loaded with doxorubicin and Kyn-degrading kynureninase to relieve immunosuppression, showing anti-tumor responses in preclinical models.
- Bo Wang
- , Jing Chen
- & Minglin Ma
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Article
| Open AccessThe genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma
The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.
- Josh N. Vo
- , Yi-Mi Wu
- & Arul M. Chinnaiyan
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Article
| Open AccessGlutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors
Small molecules that target RNA Polymerase I inhibit ribosome biogenesis to activate p53 through the nucleolar surveillance response pathway. Here, the authors show that p53 induction by ribosome stress is dependent on extracellular glutamine availability.
- Melvin Pan
- , Christiane Zorbas
- & Tsuyoshi Osawa
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Article
| Open AccessCombinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
The oncoprotein c-Myc is often overexpressed in triple negative breast cancer and has a role in tumor progression and resistance to therapy. Here the authors show that elevated MYC expression is correlated with low immune infiltration, diminished MHC-I pathway expression and that CpG/aOX40 treatment could overcome resistance to PD-L1 blockade in MYC-high breast tumors.
- Joyce V. Lee
- , Filomena Housley
- & Andrei Goga
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Article
| Open AccessRu(II) photocages enable precise control over enzyme activity with red light
The cytochrome P450 enzyme CYP1B1 is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. Here the authors describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low-energy (660 nm) light.
- Dmytro Havrylyuk
- , Austin C. Hachey
- & Edith C. Glazer
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Article
| Open AccessOccult polyclonality of preclinical pancreatic cancer models drives in vitro evolution
It is unclear if the molecular profiles of pancreatic ductal adenocarcinoma (PDAC) preclinical models remain stable during propagation. Here, the authors characterise clonal evolution throughout propagation in PDAC cell lines and a patient-derived organoid using single-cell genomics, transcriptomics and epigenomics.
- Maria E. Monberg
- , Heather Geiger
- & Anirban Maitra
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Article
| Open AccessResults of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies
G-quadruplex stabilizers, including CX-5461, exhibit synthetic lethality with loss of BRCA1/2 in preclinical models. Here the authors report the results of a phase I study of CX-5461 in patients with solid tumors enriched for DNA-repair deficiencies.
- John Hilton
- , Karen Gelmon
- & David W. Cescon
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Article
| Open AccessA scalable, open-source implementation of a large-scale mechanistic model for single cell proliferation and death signaling
Mechanistic models of how single cells respond to different perturbations can help integrate disparate big data sets or predict response to varied drug combinations. Here the authors develop a scalable, open-source pipeline for constructing and simulating large-scale, single-cell mechanistic models, an important building block for clinically-predictive mechanistic models and interpretable big data integration.
- Cemal Erdem
- , Arnab Mutsuddy
- & Marc R. Birtwistle
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Article
| Open AccessEphB4 and ephrinB2 act in opposition in the head and neck tumor microenvironment
EphrinB2 and its receptor EphB4 are highly expressed in head and neck squamous cell carcinoma (HNSCC) and disrupting EphB4-ephrinB2 interaction generates sub-optimal outcomes. Here, compartmental targeting of EphB4 and ephrinB2 in HNSCC cancer cell and endothelial compartments suggests that ephrinB2 acts as a tumor promoter and EphB4 as a tumor suppressor.
- Shilpa Bhatia
- , Diemmy Nguyen
- & Sana D. Karam
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Article
| Open AccessAddressing challenges with real-world synthetic control arms to demonstrate the comparative effectiveness of Pralsetinib in non-small cell lung cancer
Real-world data (RWD) based control arms provide an option to compare the effectiveness of single-arm trials. By performing multiple quantitative bias analyses to alleviate concerns about trial-RWD comparability, here the authors show that the RET inhibitor pralsetinib provides survival benefit in patients with RET fusion-positive non-small cell lung cancer from the ARROW single-arm trial, (NCT03037385) when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts.
- Sanjay Popat
- , Stephen V. Liu
- & Vivek Subbiah
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Article
| Open AccessARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription
Here the authors show mutation of the BAF chromatin remodeler subunit ARID1A results in an ARID1B-dependent upregulation of HERVH, an ERV required for the pluripotency regulatory network. These HERVH RNAs can partition into BRD4 foci, affecting BRD4-dependent transcription. Suppression of HERVH in colorectal cancer cells and patient-derived organoids impairs tumor growth.
- Chunhong Yu
- , Xiaoyun Lei
- & Kai Yuan
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Article
| Open AccessPilot study of bempegaldesleukin in combination with nivolumab in patients with metastatic sarcoma
The activity of PD-1 blockade in patients with sarcoma has been modest so far. Here, the authors report the results of a pilot clinical trial to assess the efficacy and safety of bempegaldesleukin, a CD122-preferential interleukin-2 (IL-2) pathway agonist, in combination with the PD1 blockade (nivolumab) in patients with locally advanced or metastatic high-grade sarcoma.
- Sandra P. D’Angelo
- , Allison L. Richards
- & William D. Tap
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Article
| Open AccessClinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets
Sarcomas are rare tumours with many different subtypes and clinical outcomes; a broader knowledge of their genetic features is required. Here, the authors analyse 2138 soft tissue and bone sarcomas across 45 subtypes using MSK-IMPACT targeted sequencing and find genomic groups that are distinct from histological subgroups.
- Benjamin A. Nacev
- , Francisco Sanchez-Vega
- & William D. Tap
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Article
| Open AccessGenetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes
Existing clinical models cannot fully capture smoldering multiple myeloma (SMM) heterogeneity. Here, integration of 42 genetic alterations from 214 SMM patients using an unsupervised binary matrix factorization clustering approach results in the identification of 6 distinct molecular and clinical subtypes.
- Mark Bustoros
- , Shankara Anand
- & Irene M. Ghobrial
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Article
| Open AccessClinical genomic profiling in the management of patients with soft tissue and bone sarcoma
Comprehensive molecular profiles are required to understand and treat sarcomas, which comprise more than 70 different subtypes. Here, the authors profile the genomic landscape of 7494 sarcomas across 44 histologies using targeted panel sequencing and identify potential therapeutic targets.
- Mrinal M. Gounder
- , Narasimhan P. Agaram
- & Dexter X. Jin
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Article
| Open AccessAutomated detection and segmentation of non-small cell lung cancer computed tomography images
Correct interpretation of computer tomography (CT) scans is important for the correct assessment of a patient’s disease but can be subjective and timely. Here, the authors develop a system that can automatically segment the non-small cell lung cancer on CT images of patients and show in an in silico trial that the method was faster and more reproducible than clinicians.
- Sergey P. Primakov
- , Abdalla Ibrahim
- & Philippe Lambin
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Article
| Open AccessA long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity
Chimeric antigen receptor T cells represent a breakthrough treatment in hematologic malignancies, but insufficient level of cytotoxicity and persistence of T cells might compromise success. Authors show here that a recombinant long acting form of interleukin-7 enhances proliferation, persistence and cytotoxicity of the engineered T cells, resulting in long term disease remission.
- Miriam Y. Kim
- , Reyka Jayasinghe
- & John F. DiPersio
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Article
| Open AccessAntigen glycosylation regulates efficacy of CAR T cells targeting CD19
Loss of surface CD19 expression by leukemic cells leads to resistance and relapse to CD19-targeted CAR-T therapies. Here the authors show that loss of SPPL3 in malignant B cells results in hyperglycosylation of CD19.
- Amanda Heard
- , Jack H. Landmann
- & Nathan Singh
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Article
| Open AccessResults of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer
FGFR-1 upregulation has been associated with endocrine therapy resistance in breast cancer patients. Here the authors report the results of a phase IIa study to assess the safety and efficacy of AZD454, an inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases, in combination with anastrozole or letrozole, in estrogen receptor positive breast cancer patients.
- R. C. Coombes
- , P. D. Badman
- & M. J. Seckl
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Article
| Open AccessDefining TCRγδ lymphoproliferative disorders by combined immunophenotypic and molecular evaluation
Tγδ large granular lymphocyte leukemia (Tγδ LGLL) is a rare lymphoproliferative neoplasm characterized by the expansion of T large granular lymphocytes expressing γδ TCR. Here, based on deep sequencing analysis of the clonotype repertoire, the authors show that leukemic Tγδ cells are characterized by recurrent public clonotypes that are diversified between symptomatic and asymptomatic patients.
- Antonella Teramo
- , Andrea Binatti
- & Renato Zambello
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Article
| Open AccessRegulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade
Immune checkpoint blockade is a promising approach to treat lung cancer, however, immune related adverse events hold back success in some patients. Here authors show that regulatory B cells fail to limit self-reactive T cells in these patients, and B cell phenotyping prior treatment may identify those at risk for these unfavourable outcomes.
- Akshay J. Patel
- , Zena N. Willsmore
- & Gary W. Middleton
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Article
| Open AccessThe drug-induced phenotypic landscape of colorectal cancer organoids
The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.
- Johannes Betge
- , Niklas Rindtorff
- & Michael Boutros
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Article
| Open AccessNuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis
Ph+ and Ph-like B-ALL remain poor prognosis leukemias. VAV3, a guanine nucleotide exchange factor, is activated and overexpressed in these leukemias. Here the authors reveal that leukemic VAV3 is predominantly nuclear. Nuclear VAV3, through its guanine nucleotide exchange factor and its effector nuclear RAC2, controls the repressive transcriptional activity of the polycomb repression complex-1 via nuclear AKT/PHLPP2 regulated BMI1.
- R. C. Nayak
- , K. H. Chang
- & J. A. Cancelas
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Article
| Open AccessSTING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer
PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.
- Qiwei Wang
- , Johann S. Bergholz
- & Jean J. Zhao
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Article
| Open AccessMulticenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer
Therapeutic options for patients with triple-negative breast cancer (TNBC) in later-line setting are limited. Here the authors report the results of a phase 2 clinical trial to evaluate efficacy and safety of the combination of camrelizumab (anti-PD1), apatinib (VEGFR2 inhibitor), and eribulin in patients with heavily pre-treated advanced TNBC.
- Jieqiong Liu
- , Ying Wang
- & Erwei Song
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Article
| Open AccessHomophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation
Direct contact between tumour cells and fibroblasts influences tumour cell behaviour. Here the authors show that pancreatic cancer cells and fibroblasts directly interact via homophilic ATP1A1 binding, which induces fibroblasts to secrete activin A to promote epithelial-mesenchymal transition of tumour cells and myofibroblast activation.
- Yi-Ing Chen
- , Chin-Chun Chang
- & Wen-Hwa Lee
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Article
| Open Accessp53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis
The failure of chemotherapy in colorectal cancer is currently unclear. Here, the authors show that upon sub-lethal dose of chemotherapy wild-type p53 colorectal cancers acquire a quiescence-like phenotype and a YAP-dependent fetal-like intestinal stem cell state associated with a higher metastatic activity and poor prognosis in patients.
- Laura Solé
- , Teresa Lobo-Jarne
- & Lluís Espinosa
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Article
| Open AccessInhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells
CDK2 can drive the proliferation of cancer cells. Here, the authors screened for a non-ATP competitive inhibitor of the CDK2/cylinA complex and find that Homoharringtonine can disrupt the complex and promote the degradation of CDK2.
- Jiawei Zhang
- , Yichao Gan
- & Wendong Huang
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Article
| Open AccessNanoparticle-enhanced radiotherapy synergizes with PD-L1 blockade to limit post-surgical cancer recurrence and metastasis
Tumor recurrence after surgical resection is associated with a poor clinical outcome. Here the authors design a manganese dioxide-based nanosystem to increase response to radio-immunotherapy by relieving tumor hypoxia and targeting myeloid cells, showing reduced post-surgical cancer recurrence and metastasis.
- Xin Guan
- , Liping Sun
- & Wenwen Yue
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Article
| Open AccessTarget receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells
The use of cell-based therapies may be helpful in eradicating cancer cells. Here, the authors generate bifunctional mesenchymal stem cells and demonstrate their therapeutic efficacy in glioblastoma patient-derived models.
- Deepak Bhere
- , Sung Hugh Choi
- & Khalid Shah
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Article
| Open AccessA deep learning model and human-machine fusion for prediction of EBV-associated gastric cancer from histopathology
Epstein–Barr virus-associated gastric cancer shows a robust response to immune checkpoint inhibitors. Here the authors introduce a deep convolutional neural network and its fusion with pathologists for predicting it from histopathology.
- Xueyi Zheng
- , Ruixuan Wang
- & Muyan Cai
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Article
| Open AccessReversing insufficient photothermal therapy-induced tumor relapse and metastasis by regulating cancer-associated fibroblasts
Photothermal therapy (PTT) has emerged as a promising approach for cancer treatment. Here, in preclinical cancer models, the authors show that PTT efficacy could be improved using tumor cell-derived microparticles that co-deliver the photosensitizer indocyanine green and a vitamin-D receptor ligand, calcipotriol, resulting in tumor extracellular matrix remodelling and ameliorated anti-tumor immune responses.
- Xin Li
- , Tuying Yong
- & Xiangliang Yang