Featured
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| Open AccessSingle-cell microRNA sequencing method comparison and application to cell lines and circulating lung tumor cells
Technologies for small non-coding RNA sequencing at the single-cell level are less mature than for sequencing mRNAs. Here the authors evaluate available protocols for analysis of circulating lung cancer tumour cells.
- Sarah M. Hücker
- , Tobias Fehlmann
- & Stefan Kirsch
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Article
| Open AccessNotch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer
Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC) and the mechanisms driving benefit are poorly understood. Here, the authors show that elevated Notch signaling predicts clinical benefit in ICB in relapsed SCLC.
- Nitin Roper
- , Moises J. Velez
- & Anish Thomas
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Article
| Open AccessComprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories
Formalin-fixed, paraffin-embedded (FFPE) specimens are an attractive resource for retrospective clinical proteomics studies. Here, the authors benchmark and optimize proteomics workflows for FFPE sample analysis and provide guidelines on which methods to use for different samples and applications.
- Corinna Friedrich
- , Simon Schallenberg
- & Philipp Mertins
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Article
| Open AccessImmune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features
The evolution of immune landscape in lung adenocarcinoma (ADC) is largely unknown. Here the authors use a cohort of resected invasive lung ADC and its precursors and show a gradual increase of immunosuppression and decrease of anti-tumor response associated with specific genomic and epigenetic features.
- Hitoshi Dejima
- , Xin Hu
- & Jianjun Zhang
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Article
| Open AccessAn RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness
Activated Notch signalling promotes cancer metastasis and stemness. Here the authors show that Notch1 activates transcription of DNA replication factor RCF4 and that RCF4 binds and stabilises Notch1 intracellular domain (NICD1) to promote cancer metastasis.
- Lei Liu
- , Tianyu Tao
- & Han Tian
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Article
| Open AccessLung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week
The lengthy time in establishing patient-derived organoids(PDOs) hampers the implementation of PDO-based drug sensitivity tests in clinics. Here, the authors show a microwell array-based method to predict patient’s responses to anti-cancer therapies in a week using lung cancer organoids.
- Yawei Hu
- , Xizhao Sui
- & Peng Liu
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Article
| Open AccessTh17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers
Recent clinical trials combining MEK inhibitors with anti-PD-L1 in solid tumours show moderate responses. Here, the authors demonstrate that the combination of MEK inhibition and PD-L1 blockade in KRAS mutant lung cancer models leads to a transient tumour regressions and resistance due to increased infiltration of Th17 cells and that the triple therapy targeting MEK, PD-L1 and IL-17 produced better in vivo responses.
- David H. Peng
- , B. Leticia Rodriguez
- & Don. L. Gibbons
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Article
| Open AccessSingle-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer
Comprehensive profiles of tumour and microenvironment are critical to understand heterogeneity in non-small cell lung cancer (NSCLC). Here, the authors profile 42 late-stage NSCLC patients with single-cell RNA-seq, revealing immune landscapes that are associated with cancer subtype or heterogeneity.
- Fengying Wu
- , Jue Fan
- & Caicun Zhou
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Article
| Open AccessA data-independent acquisition-based global phosphoproteomics system enables deep profiling
Phosphoproteomics can provide systematic insights into disease-associated cell signaling changes. Here, the authors present a sensitive workflow integrating library-based and direct data-independent acquisition approaches, and a hybrid spectral library resource for in-depth phosphoproteomic profiling.
- Reta Birhanu Kitata
- , Wai-Kok Choong
- & Yu-Ju Chen
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Article
| Open AccessSOD1 regulates ribosome biogenesis in KRAS mutant non-small cell lung cancer
The superoxide dismutase SOD1 is highly expressed in lung cancer but its role has not fully investigated yet. In this study, the authors demonstrate that SOD1 regulates ribosome biogenesis driving KRAS-driven lung tumorigenesis.
- Xiaowen Wang
- , Hong Zhang
- & X. F. Steven Zheng
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Article
| Open AccessEpigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T cell-mediated cytotoxicity in lung cancer
Gamma delta (γδ) T cells have potential for use in immunotherapy against tumours. Here, the authors demonstrate that treatment of tumours with DNA methyltransferase inhibitors modulates cytoskeleton arrangements, upregulates adhesion molecules and increases tumour killing by γδ T cells.
- Rueyhung R. Weng
- , Hsuan-Hsuan Lu
- & Hsing-Chen Tsai
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Article
| Open AccessFerroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes
The high degree of subtype plasticity in small cell lung cancer (SCLC) poses a therapeutic challenge. Here, the authors show that the non-neuroendocrine (non-NE) subtype of SCLC is sensitive to ferroptosis while the neuroendocrine (NE) subtype is vulnerable to TRX anti-oxidant pathway inhibition, and the combination of these two treatments in SCLC circumvents non-NE/NE subtype plasticity.
- Christina M. Bebber
- , Emily S. Thomas
- & Silvia von Karstedt
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Article
| Open AccessA KRAS-responsive long non-coding RNA controls microRNA processing
Wild-type KRAS amplification is known to induce KRAS activation in cancer leading to poor prognostic outcomes. Here the authors identify a KRAS-responsive lncRNA, KIMAT1 that maintains KRAS signalling in lung cancer, suggesting that its targeting may prevent KRAS-driven tumourigenesis.
- Lei Shi
- , Peter Magee
- & Michela Garofalo
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Article
| Open AccessStructure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting
An EGFR mutant with kinase domain duplication (EGFR-KDD) was previously identified in an index patient, but the functional and therapeutic implications remain unclear. Here, the authors show that KDD occurs in other ErbB receptors in multiple cancers, and characterize the mechanism and inhibition of EGFR-KDD.
- Zhenfang Du
- , Benjamin P. Brown
- & Christine M. Lovly
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Article
| Open AccessGilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer
Resistance to ALK inhibitors such as lorlatinib often arise due to on-target mutations. Here, the authors show the multi-kinase inhibitor gilteritinib is effective against different mutations that arise during lorlatinib in ALK fusion positive lung cancer to cause resistance.
- Hayato Mizuta
- , Koutaroh Okada
- & Ryohei Katayama
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Article
| Open AccessThe oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3
The mechanisms of how gain-of-function (GOF) mutant p53 drives carcinogenesis are unclear. Here, the authors show that a GOF mutant p53 requires its transactivation capability to induce mouse lung tumors and this is dependent on PLK3 phosphorylation of GOF mutant p53.
- Catherine A. Vaughan
- , Shilpa Singh
- & Sumitra Deb
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Article
| Open AccessEvolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas
It is known that invasive lung adenocarcinomas evolve from pre-cancerous dysplastic lesions. In this study, the authors show that evolution of pre-cancerous lesions is accompanied by DNA methylation alterations, and that global hypomethylation correlates with immune infiltration, mutational burden and copy number alterations.
- Xin Hu
- , Marcos R. Estecio
- & Jianjun Zhang
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Article
| Open AccesscircNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity
Circular RNAs (circRNA) is a class of non-coding RNAs that can regulate gene translation and function. Here the authors show that a circRNA, circNDUFB2, is downregulated in non-small cell lung cancer tissues, and likely contributes to anti-tumor immunity by regulating both degradation of oncoproteins and induction of innate immunity.
- Botai Li
- , Lili Zhu
- & Wenxin Qin
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Article
| Open AccessTumor evolutionary trajectories during the acquisition of invasiveness in early stage lung adenocarcinoma
Invasive early stage lung adenocarcinoma has a heterogeneous prognosis. Here, the authors microdissect malignant pulmonary nodules to invasive and preinvasive components and study the mutations that are common or private between the lesions, allowing them to understand the evolutionary path of the tumours.
- Siwei Wang
- , Mulong Du
- & Rong Yin
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Article
| Open AccessEnhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers
Aberrant activation of NRF2 in cancer cells contributes to tumorigenicity and therapeutic resistance. Here, the authors show that NRF2 cooperates with CEBPB and remodels enhancers to confer tumor-initiating activity on NRF2- activated non-small cell lung cancers.
- Keito Okazaki
- , Hayato Anzawa
- & Hozumi Motohashi
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Article
| Open AccessNon-invasive decision support for NSCLC treatment using PET/CT radiomics
EGFR mutations are common in non-small cell lung cancer and patients with these mutations are treated with tyrosine kinase inhibitors. Here, the authors show that EGFR mutation status can be predicted from 18F-FDG-PET/CT images, which may enable the stratification of patients for treatment.
- Wei Mu
- , Lei Jiang
- & Matthew B. Schabath
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Article
| Open AccessAKT-induced lncRNA VAL promotes EMT-independent metastasis through diminishing Trim16-dependent Vimentin degradation
The role of long non-coding RNA (lncRNA) in AKT-driven tumor development is unclear. Here, the authors identify VAL (Vimentin associated lncRNA) to be directly induced by AKT/STAT3 signaling and report a lncRNA-mediated mechanism for active AKT-driven EMT-independent lung adenocarcinoma metastasis.
- Han Tian
- , Rong Lian
- & Junchao Cai
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Article
| Open Accessc-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis
c-Myc and p53 operate in a negative feedback manner to maintain cellular homeostasis. Here, the authors report a long noncoding RNA, MILIP as a downstream target of c-Myc and that MILIP represses p53 to support tumorigenicity.
- Yu Chen Feng
- , Xiao Ying Liu
- & Lei Jin
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Article
| Open AccessPINCH-1 regulates mitochondrial dynamics to promote proline synthesis and tumor growth
Proline metabolism is crucial to tumor proliferation. Here, the authors show PINCH-1 deficiency inhibited proline synthesis by promoting mitochondrial fragmentation via DRP1, downregulating PYCR1 expression and reducing cell proliferation in vitro and in vivo.
- Ling Guo
- , Chunhong Cui
- & Chuanyue Wu
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Article
| Open AccessIntegrated molecular characterization reveals potential therapeutic strategies for pulmonary sarcomatoid carcinoma
Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here the authors performed multi-omics analysis of human samples to investigate the mutational landscape of PSC and show three subgroups of PSC with distinct biology, prognosis and potential therapeutic strategies.
- Zhenlin Yang
- , Jiachen Xu
- & Jie He
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Article
| Open AccessTransient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer
Cancer cells develop resistance to tyrosine kinase inhibitors targeting EGFR. Here, the authors explore the mechanism of resistance to one such inhibitor - osimertinib - and find that resistance is caused by increased expression and activation of the IGF1 receptor and subsequent activation of the donwstream signalling pathway.
- Rong Wang
- , Tadaaki Yamada
- & Seiji Yano
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Article
| Open AccessMCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically
Cancer cells frequently harbour genetic aberrations that protect them from programmed cell death. Here, the authors show in non-small cell lung cancer that the anti-apoptotic gene MCL-1 is subject to copy number gains and that deletion of MCL-1 reduces tumour formation.
- Enkhtsetseg Munkhbaatar
- , Michelle Dietzen
- & Philipp J. Jost
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Article
| Open AccessCollagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion
Tumor extracellular matrix has been associated with cancer progression, therapy resistance and immune suppression. Here, the authors show that collagen generates resistance to PD-1/PD-L1 immunotherapy by upregulating LAIR1 expression and downstream signaling, leading to increased CD8+ T cell exhaustion.
- David H. Peng
- , Bertha Leticia Rodriguez
- & Don L. Gibbons
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Article
| Open AccessRapid, deep and precise profiling of the plasma proteome with multi-nanoparticle protein corona
Large-scale, unbiased proteomics studies of biological samples like plasma are constrained by the complexity of the proteome. Herein, the authors develop a highly parallel protein quantitation platform leveraging multi nanoparticle protein coronas for deep proteome sampling and biomarker discovery.
- John E. Blume
- , William C. Manning
- & Omid C. Farokhzad
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Article
| Open AccessTRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target
Depletion of tribbles pseudokinase 3 (TRIB3) is known to suppress the expression of several tumor-promoting factors, including EGFR. Here, the authors show that TRIB3 interacts with EGFR and regulates its stability and activity, and perturbing EGFR-TRIB3 interaction attenuates NSCLC progression by accelerating EGFR degradation.
- Jiao-jiao Yu
- , Dan-dan Zhou
- & Zhuo-Wei Hu
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Article
| Open AccessMultiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours
A drug used at the maximum tolerated dose can exert a strong selective pressure on cancer cells leading to resistance. In this study, the authors demonstrate the efficacy of using low dose of multiple drugs for preventing and treating resistance to EGFR tyrosine kinase inhibitors in NSCLC cells.
- João M. Fernandes Neto
- , Ernest Nadal
- & René Bernards
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Article
| Open AccessGenetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma
Many tumors are known to be heterogeneous. Here, the authors examined multiple samples from 84 patients with lung adenocarcinoma and demonstrate that the intratumor heterogeneity of methylation and copy number associates with poor prognosis.
- Xing Hua
- , Wei Zhao
- & Maria Teresa Landi
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Article
| Open AccessResistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures
Acquired resistance to cancer therapies reflects the ability of cancers to adapt to therapy-imposed selective pressures. Here, the authors elucidate the dynamics of developing resistance to ALK inhibitors in an ALK+ lung cancer cell line showing that resistance originates from drug-specific tolerant cancer cells and it develops as a gradual adaptation.
- Robert Vander Velde
- , Nara Yoon
- & Andriy Marusyk
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Article
| Open AccessSingle-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma
Understanding the mechanisms that lead to lung adenocarcinoma metastasis is important for identifying new therapeutics. Here, the authors document the changes in the transcriptome of human lung adenocarcinoma using single-cell sequencing and link cancer cell signatures to immune cell dynamics.
- Nayoung Kim
- , Hong Kwan Kim
- & Hae-Ock Lee
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Article
| Open AccessExploiting evolutionary steering to induce collateral drug sensitivity in cancer
Evolutionary steering uses therapies to control tumour evolution by exploiting trade-offs. Here, using a barcoding approach applied to large cell populations, the authors explore evolutionary steering in lung cancer cells treated with EGFR inhibitors.
- Ahmet Acar
- , Daniel Nichol
- & Andrea Sottoriva
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Article
| Open AccessThe X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage
Alternate splicing of mRNA precursors has been linked to tumor development. Here the authors reveal a role of the E3 ligase RNF113A in spliceosome regulation affecting cell survival upon DNA damage.
- Kateryna Shostak
- , Zheshen Jiang
- & Alain Chariot
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Article
| Open AccessMEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response
Loss ofMEN1 results in an inherited multiple endocrine neoplastic type 1 syndrome. Here, the authors generate an alveolar type II cell MEN1 knockout mouse model and show that on a Kras mutant background the mice develop lung tumors with features of neuroendocrine differentiation.
- Huan Qiu
- , Bang-Ming Jin
- & Guang-Hui Jin
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Article
| Open AccessPan-cancer characterization of immune-related lncRNAs identifies potential oncogenic biomarkers
In cancer, long noncoding RNAs (lncRNAs) can regulate immune-related pathways. Here, the authors present ImmLnc, an algorithm that can help prioritise immune-related lncRNAs in cancer immunotherapy research
- Yongsheng Li
- , Tiantongfei Jiang
- & Xia Li
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Article
| Open AccessComprehensive T cell repertoire characterization of non-small cell lung cancer
Relevant features of T cell repertoire in human cancer remain to be delineated. Here the authors show, by TCR sequencing in a large cohort of lung cancer patients, that while a majority of T cell clones are shared between tumor and adjacent lung tissue, less frequent tumor-unique T cell clones correlate with worse prognosis.
- Alexandre Reuben
- , Jiexin Zhang
- & Jianjun Zhang
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Article
| Open AccessYAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation
Relapse is a limitation for the efficacy of the anaplastic lymphoma kinase (ALK)-inhibitor alectinib in ALK-rearranged lung cancer. Here, the authors show that YAP1 activation upon alectinib treatment leads to therapy resistance and that inhibiting both YAP1 and ALK leads to longer tumor remission in mice.
- Takahiro Tsuji
- , Hiroaki Ozasa
- & Toyohiro Hirai
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Article
| Open AccessRecurrent PTPRT/JAK2 mutations in lung adenocarcinoma among African Americans
Lung cancer etiology has largely been studied in homogenous populations of European descent. Here, targeted sequencing in African American lung adenocarcinomas finds significantly higher prevalence of PTPRTand JAK2 mutations, validated independently by whole exome sequencing, highlighting potentially clinically actionable mutations in this population.
- Khadijah A. Mitchell
- , Noah Nichols
- & Bríd M. Ryan
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Article
| Open AccessFunctional significance of U2AF1 S34F mutations in lung adenocarcinomas
The authors report a co-occurrence of the U2AF1 S34F splicing factor mutation and ROS1 translocations in lung adenocarcinomas and profile effects of S34F on transcriptome-wide RNA binding. They further show that U2AF1 S34F enhances invasive potential and alters splicing of ROS1 fusion transcripts
- Mohammad S. Esfahani
- , Luke J. Lee
- & Maximilian Diehn
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Article
| Open AccessEliminating blood oncogenic exosomes into the small intestine with aptamer-functionalized nanoparticles
Oncogenic exosomes can circulate in the blood, but their selective removal has not been possible. Here the authors show that aptamer-functionalised mesoporous silica nanoparticles can find to a specific population of circulating exosomes and eliminate them via the hepatobiliary route.
- Xiaodong Xie
- , Huifang Nie
- & Lee Jia
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Article
| Open AccessA high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells
Many cancer cells have increased glucose consumption compared to normal cells, a feature that can be exploited therapeutically. Here, the authors carry out a chemical screen and identify compounds that selectively blocks glucose metabolism in non-small-cell lung cancer cell lines.
- Chiara Ghezzi
- , Alicia Wong
- & Peter M. Clark
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Article
| Open AccessEpithelial tumor suppressor ELF3 is a lineage-specific amplified oncogene in lung adenocarcinoma
Tissue context can dictate why a gene can have seemingly opposing functions in different settings. ELF3 is tumor suppressive in many cancers of epithelial origin but in lung cancer, the authors describe an oncogenic role in the adenocarcinoma histology of non-small cell lung cancer.
- Katey S. S. Enfield
- , Erin A. Marshall
- & Wan L. Lam
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Article
| Open AccessCausative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance
PDLIM2 is repressed epigenetically in lung cancers, which are frequently resistant to anti-PD-1/PD-L1 and chemotherapy. Here, the authors describe the mechanism through which epigenetic restoration of PDLIM2 synergises with anti-PD-1 and chemotherapy in lung cancers.
- Fan Sun
- , Liwen Li
- & Zhaoxia Qu
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Article
| Open AccessZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer
Non-small cell lung cancer (NSCLC) is often associated with metastasis to the lungs. Here, the authors perform independent screens and identify NuRD as a co-repressor of ZEB1, and demonstrate TBC1D2b as a downstream target of ZEB1/NuRD complex regulating NSCLC metastasis.
- Roxsan Manshouri
- , Etienne Coyaud
- & Don L. Gibbons
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Article
| Open AccessNestin regulates cellular redox homeostasis in lung cancer through the Keap1–Nrf2 feedback loop
Loss of Nestin sensitizes non-small cell lung carcinoma (NSCLC) to oxidative stress. Here, the authors report a feedback loop between Nestin and Nrf2 wherein Nestin competes with Nrf2 for Keap1 binding, preventing Nrf2 degradation, and show the Nestin–Keap1–Nrf2 axis to regulate redox homeostasis in NSCLC.
- Jiancheng Wang
- , Qiying Lu
- & Andy Peng Xiang
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Article
| Open AccessYTHDF1 links hypoxia adaptation and non-small cell lung cancer progression
Hypoxia occurs at high altitude and in cancer. Here, the authors show that a gene involved in hypoxia, YTHDF1, underwent rapid evolution in Tibetans and their domestic animals, and find that the gene is amplified in some cancers and contributes to drug resistance in hypoxic conditions.
- Yulin Shi
- , Songqing Fan
- & Yongbin Chen