The development of pancreatic cancer is heavily dependent upon the aberrant activation of KRAS signaling. Among the downstream targets of KRAS, the effectors of the Hippo pathway YAP and TAZ ...(YAP/TAZ) are crucial during cancer initiation and progression. However, little is known about the cell type-specific effects of YAP/TAZ on the development of pancreatic cancer. Here we clarify the unique consequences of YAP/TAZ activation in the ductal cell population of the pancreas by generating mice with pancreatic duct cell-specific, inducible knockouts of
and
, the main kinases upstream of YAP/TAZ. Oncogenic activation of YAP by deletion of
in ductal cells led to the rapid transformation of the pancreas, which was accompanied by a robust increase in the expression of YAP and AP-1 target genes. Pharmacologic inhibition of AP-1 activity induced death in
knockout organoids and attenuated YAP-dependent transformation of the pancreas
. Both YAP and AP-1 were activated during the development of KRAS-dependent cancer in mice and human patients with pancreatic ductal adenocarcinoma, suggesting that this signaling hub represents an important mediator of pancreatic cancer development and progression. Collectively, these data define a YAP-dependent mechanism of pancreatic cancer cell development and suggest that inhibition of AP-1 can suppress this development. SIGNIFICANCE: A pancreatic ductal cell-specific knockout mouse model featuring constitutively active YAP allows for the study of YAP-dependent transformation of the pancreas and for screening pharmacologically active inhibitors.
Yes‐associated protein (YAP) and myocardin‐related transcription factor (MRTF) play similar roles and exhibit significant crosstalk in directing transcriptional responses to chemical and physical ...extracellular cues. The mechanism underlying this crosstalk, however, remains unclear. Here, we show MRTF family proteins bind YAP via a conserved PPXY motif that interacts with the YAP WW domain. This interaction allows MRTF to recruit NcoA3 to the TEAD‐YAP transcriptional complex and potentiate its transcriptional activity. We show this interaction of MRTF and YAP is critical for LPA‐induced cancer cell invasion in vitro and breast cancer metastasis to the lung in vivo. We also demonstrate the significance of MRTF‐YAP binding in regulation of YAP activity upon acute actin cytoskeletal damage. Acute actin disruption induces nucleo‐cytoplasmic shuttling of MRTF, and this process underlies the LATS‐independent regulation of YAP activity. Our results provide clear evidence of crosstalk between MRTF and YAP independent of the LATS kinases that normally act upstream of YAP signaling. Our results also suggest a mechanism by which extracellular stimuli can coordinate physiological events downstream of YAP.
Synopsis
Oncogenic activity of TEAD‐YAP transcription complex is enhanced by MRTF proteins, which recruit NcoA3. MRTF–YAP interaction highlights a novel mode of signal transduction that regulates YAP activity independently of subcellular localization.
MRTF family proteins activate TEAD‐YAP by direct binding through PPXY–WW domain interaction.
MRTF–YAP interaction is required for TEAD‐YAP target gene expression and promotion of cancer cell invasion and metastasis.
MRTF binding to TEAD‐YAP recruits NcoA3 for full potentiation of TEAD‐YAP activity.
MRTF–YAP interaction constitutes a LATS‐independent regulatory mechanism on TEAD‐YAP activity.
Crosstalk with transcription factor MRTF enhances TEAD‐YAP oncogenic activity, coordinating signal transduction of extracellular GPCR ligands involved in cancer cell invasion or actin cytoskeletal disruption.
The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired ...resistance after EGFR-TKI treatment, and primary resistance marked by cancer cell's dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.
•YAP plays a crucial role in the EGFR-TKI resistance of lung adenocarcinoma.•YAP increases the expression of AXL that induces the resistance to EGFR-TKI in lung adenocarcinoma.•Increased YAP expression in gefitinib resistant cells is independent of the canonical Hippo pathway.•Combination of YAP inhibitor and EGFR-TKI can be helpful for overcoming the EGFR-TKI resistance.
Image segmentation techniques based on machine learning are able to improve diagnostic and therapeutic accuracy by localizing target areas. The accuracy and efficiency of these techniques are ...dependent on network architecture and loss minimization method because the performance of a machine learning model is determined by training strategies. In this study, the lung segmentation based on computed tomographic images was performed by using mask regional convolutional neural networks (R-CNNs) with various feature extraction networks and optimizers. The effects of the feature extraction networks and optimizers on the trained mask R-CNNs were evaluated in terms of total training loss, segmentation accuracy and training time. The results showed that the convergence of total loss values during network training was affected by the architectures of the feature extraction networks as well as the optimizers. The lung segmentation accuracy and training time of the mask R-CNN were mainly dependent on the optimizer and network architecture, respectively. Among the various optimizers, the ASGD optimizer maximized lung segmentation accuracy, and the training time was reduced by the feature extraction network including general convolution layers and feature pyramid network (FPN). In conclusion, it is important to apply the optimal network architecture and optimizer to the mask R-CNN for maximizing its performance, and the optimized mask R-CNN can be potentially used for improving diagnostic and therapeutic accuracy.
Lung cancer organoid (LCO) is a novel model of lung cancer that facilitates drug screening. However, the success rate of LCOs varies from 7% to 87%, and the culture medium compositions are markedly ...different. Airway organoid media can be used for LCO cultures, but this promotes the overgrowth of normal cell organoids especially in LCOs from intrapulmonary lesions. Several modified media are specifically utilized for promoting the cancer cell's growth. For culturing high-purity LCOs, cancer cells from metastatic lesions and malignant effusions are used. Recently, single-cell RNA sequencing has identified previously unknown cell populations in the lungs and lung cancer. This sequencing technology can be used to validate whether the LCO recapitulates the heterogeneity and functional hierarchy of the primary tumor. Several groups have attempted to culture LCOs with mesenchymal cells and immune cells to recapitulate the tumor microenvironment. Disease modeling using LCO provides novel insight into the pathophysiology of lung cancer and enables high-throughput screening for drug discovery and prognosis prediction. An LCO model would help to identify new concepts as a basis for lung cancer targeting by discovering innovative therapeutic targets.
There is an unmet need for biomarkers for the diagnosis of lung cancer and decision criteria for lung biopsy. We comparatively investigated the lung microbiomes of patients with lung cancer and ...benign lung diseases. Patients who underwent bronchoscopy at Chungnam National University Hospital between June 2021 and June 2022 were enrolled. Bronchoalveolar lavage fluid (BALF) was collected from 24 patients each with lung cancer and benign lung diseases. The samples were analyzed using 16S rRNA-based metagenomic sequencing. We found that alpha diversity and the beta diversity distribution (P = 0.001) differed significantly between patients with benign lung diseases and those with lung cancer. Firmicutes was the most abundant phylum in patients with lung cancer (33.39% ± 17.439), whereas Bacteroidota was the most abundant phylum in patients with benign lung disease (31.132% ± 22.505), respectively. In differential abundance analysis, the most differentially abundant microbiota taxon was unclassified_SAR202_clade, belonging to the phylum Chloroflexi. The established prediction model distinguished patients with benign lung disease from those with lung cancer with a high accuracy (micro area under the curve AUC = 0.98 and macro AUC = 0.99). The BALF microbiome may be a novel biomarker for the detection of lung cancer.
The coronavirus disease (COVID-19) outbreak has prompted various industries to embark on digital transformation efforts, with software playing a critical role. Ensuring the reliability of software is ...of the utmost importance given its widespread use across multiple industries. For example, software has extensive applications in areas such as transportation, aviation, and military systems, where reliability problems can result in personal injuries and significant financial losses. Numerous studies have focused on software reliability. In particular, the software reliability growth model has served as a prominent tool for measuring software reliability. Previous studies have often assumed that the testing environment is representative of the operating environment and that software failures occur independently. However, the testing and operating environments can differ, and software failures can sometimes occur dependently. In this study, we propose a new model that assumes uncertain operating environments and dependent failures. In other words, the model proposed in this study takes into account a wider range of environments. The numerical examples in this study demonstrate that the goodness of fit of the new model is significantly better than that of the existing SRGM. Additionally, we show the utilization of the sequential probability ratio test (SPRT) based on the new model to assess the reliability of the dataset.
We suggest an electrochemiluminescence (ECL)-sensing platform driven by ecofriendly, disposable, and miniaturized reverse electrodialysis (RED) patches as an electric power source. The flexible RED ...patches composed of ion-exchange membranes (IEMs) can produce voltage required for ECL sensing by simply choosing the appropriate number of IEMs and the ratio of salt concentrations. We integrate the RED patch with a bipolar electrode on the microfluidic chip to demonstrate the proof-of-concept, i.e., glucose detection in the range of 0.5–10 mM by observing ECL emissions with naked eyes. The miniaturized RED-powered biosensing system is widely applicable for electrochemical-sensing platforms. This is expected to be a solution for practical availability of battery-free electrochemical sensors for disease diagnosis in developing countries.
Background
Oligonucleotide therapeutics have emerged as a promising and dynamic class of pharmaceutical agents with remarkable potential for treating a wide spectrum of genetic and acquired diseases. ...These therapeutic entities, comprising short nucleic acid sequences of either ribonucleic acids (RNA) or deoxyribonucleic acids (DNA), offer the distinct advantage of precise targeting and the ability to interfere with disease-causing genes or proteins. Despite their inherent therapeutic potential, their clinical utility has been hampered by various challenges, including rapid degradation, limited cellular uptake, and unintended immune responses.
Area covered
Chemical modification strategies have been extensively explored to overcome these limitations and enhance their pharmacological properties. In this review, we provide a comprehensive overview of oligonucleotide therapeutics and their associated chemical modification approaches, highlighting their potential in the clinical realm.
Expert opinion
By elucidating the progress made in chemical modifications and their implications for clinical translation, we seek to highlight the pivotal role of these strategies in realizing the full therapeutic potential of oligonucleotide-based therapies for treating a wide range of diseases.
Oral probiotics have been recently gaining much attention owing to their potential to inhibit the progression of dental caries by controlling the cariogenic effects of Streptococcus mutans. We ...isolated and genotypically identified 77 lactic acid bacteria including 12 Limosilactobacillus fermentum probiotic candidates from the oral cavity of healthy volunteers. Among the 12 L. fermentum isolates, nine isolates effectively inhibited the growth of S. mutans via hydrogen peroxide (H
O
) production. The others neither suppressed the growth of S. mutans nor produced H
O
. Eight out of the nine H
O
-producing L. fermentum isolates exhibited strong adherence to oral epithelial KB cells while inhibiting the adherence of S. mutans to KB cells. The eight H
O
-producing isolates were neither haemolytic based on a blood-agar test, cytotoxic according to lactate dehydrogenase assay, nor resistant to eight antibiotics represented by the European Food Safety Authority guideline, indicating that the isolates have potential to suppress the cariogenesis driven by S. mutans while providing general probiotic benefits.
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