Biology subjects

Jeong, H. J.

Publications and source records attributed to Jeong, H. J..

5 recordsLinked to original sources

bioRxiv2025

GraphTME: a framework for predicting response to immune checkpoint inhibitors by interpreting cell-cell interactions in the tumour microenvironment using spatial transcriptomics of tumour tissue

Immune checkpoint inhibitors (ICIs) have been used to treat cancer by reactivating T-cell responses against tumours, yet clinical efficacy remains limited due to low response rates and the lack of robust predictive biomarkers. The tumour microenvironment critically shapes ICI responsiveness by modulating antitumour immunity, necessitating a deeper understanding of spatially organised cell-cell interactions. Imaging-based spatial transcriptomics (ST) enables such analysis at single-cell resolution. We present GraphTME, a spatially informed and biologically interpretable framework that models pathway-specific directional cell-cell interactions to predict anti-PD-1 response. Ligand-receptor interactions are organised by signalling pathways and represented as a multi-relational directed graph, with edge weights inversely scaled by spatial distance. Using CD8+ T cells from single-cell RNA-seq data of ICI-treated NSCLC patients, we trained a relational graph convolutional network to infer immune responsiveness. GraphTME achieved an F1 score exceeding 0.83 in predicting ICI response and was validated using MERFISH data from an NSCLC patient with a partial response. Predicted responder CD8+ T cells exhibited higher abundance and stronger directional signalling to tumour cells. They also expressed genes associated with antitumour activity, while non-responders showed expression patterns linked to poor prognosis. GraphTME is the first framework to quantitatively model single-cell-level interactions within the spatial architecture of tumour tissues and predict ICI responses from these interactions. It offers a spatially resolved, biologically grounded biomarker for immunotherapy and a tool for dissecting immune dynamics in situ.

bioinformatics↗

bioRxiv2021

JAG1 intracellular domain acts as a transcriptional cofactor that forms an oncogenic transcriptional complex with DDX17/SMAD3/TGIF2

Jagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, such as the formation of NOTCH1 intracellular domain (NICD1), however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Herein, we revealed that JICD1 induced astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to chemotherapy and radiotherapy. The transcriptome, ChIP-sequencing, and proteomic analyses revealed that JICD1 increased SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. Furthermore, JICD1-driven tumorigenicity was directly regulated by SOX2. Therefore, our results demonstrated that, like NICD1, JICD1 acts as a transcriptional cofactor in the formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.

molecular biology↗

bioRxiv2020

Inhibition of lysyl oxidase-like 2 ameliorates folic acid-induced renal tubulointerstitial fibrosis

Tubulointerstitial fibrosis is characterized by accumulation of the extracellular matrix in the interstitium. Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family, is known for promoting cancer metastasis, invasion, and stromal fibrosis in various organs. Our previous study demonstrated expression of LOXL2 in kidney podocytes and tubular epithelial cells, and the association between elevated LOXL2 and tubulointerstitial fibrosis. The present study evaluated the effect of LOXL2 inhibition using an inhibitory monoclonal antibody (AB0023) on tubulointerstitial fibrosis in a folic acid-induced tubulointerstitial fibrosis mouse model. We also evaluated the association of LOXL2 with epithelial-mesenchymal transformation related molecules in vitro using HK-2 cells. Our data demonstrate that AB0023 prevented the progression of tubulointerstitial fibrosis significantly, as determined by trichrome and picro-sirius red staining, as well as the total collagen assay. The mean expression of phosphorylated Smad2 and Smad4 was lower in the AB0023-treated group although it was not statistically significant. Following transforming growth factor-{beta} (TGF-{beta}) challenge, LOXL2-deficient HK-2 cells exhibited significantly lower expression of the mesenchymal markers vimentin and fibronectin than control HK-2 cells. In conclusion, LOXL2 inhibition ameliorates renal fibrosis through the TGF-{beta}/Smad signalling pathway.

pathology↗

bioRxiv2020

Criterion Validity and Relationships between Alternative Hierarchical Dimensional Models of General and Specific Psychopathology

Psychopathology can be viewed as a hierarchy of correlated dimensions. Many studies have supported this conceptualization, but they have used alternative statistical models with differing interpretations. In bifactor models, every symptom loads on both the general factor and one specific factor (e.g., internalizing), which partitions the total explained variance in each symptom between these orthogonal factors. In second-order models, symptoms load on one of several correlated lower-order factors. These lower-order factors load on a second-order general factor, which is defined by the variance shared by the lower-order factors. Thus, the factors in second-order models are not orthogonal. Choosing between these valid statistical models depends on the hypothesis being tested. Because bifactor models define orthogonal phenotypes with distinct sources of variance, they are optimal for studies of shared and unique associations of the dimensions of psychopathology with external variables putatively relevant to etiology and mechanisms. Concerns have been raised, however, about the reliability of the orthogonal specific factors in bifactor models. We evaluated this concern using parent symptom ratings of 9-10 year olds in the ABCD Study. Psychometric indices indicated that all factors in both bifactor and second-order models exhibited at least adequate construct reliability and estimated replicability. The factors defined in bifactor and second-order models were highly to moderately correlated across models, but have different interpretations. All factors in both models demonstrated significant associations with external criterion variables of theoretical and clinical importance, but the interpretation of such associations in second-order models was ambiguous due to shared variance among factors. General Scientific SummarySome investigators have proposed that viewing the correlated symptoms of psychopathology as a hierarchy in which all symptoms are related to both a general (p) factor of psychopathology and a more specific factor will make it easier to distinguish potential risk factors and mechanisms that are nonspecifically related to all forms of psychopathology versus those that are associated with specific dimensions of psychopathology. Parent ratings of child psychopathology items from the Adolescent Brain Cognitive Development (ABCD) Study were analyzed using two alternative statistical models of the proposed hierarchy. All factors of psychopathology defined in both bifactor and second-order models demonstrated adequate psychometric properties and criterion validity, but associations of psychopathology factors with external variables were more easily interpreted in bifactor than in second-order models.

neuroscience↗

bioRxiv2019

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

EML4-ALK is an oncogenic fusion present in [~]5% lung adenocarcinomas. However, distinct EML4-ALK variants differ in the length of the EML4 microtubule-associated protein encoded within the fusion and are associated with a poorly understood variability in disease progression and therapeutic response. Here, we show that EML4-ALK variant 3, which is linked to accelerated metastatic spread and worse patient outcome, causes microtubule stabilization, formation of extended cytoplasmic protrusions, loss of cell polarity and increased cell migration. Strikingly, this is dependent upon the NEK9 kinase that interacts with the N-terminal region of EML4. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates cell migration in a manner that requires the downstream kinase NEK7 but not ALK activity. Moreover, elevated NEK9 is associated in patients with EML4-ALK V3 expression, as well as reduced progression-free and overall survival. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through recruitment of NEK9 and NEK7 to increase cell migration and that this represents a novel actionable pathway that drives disease progression in lung cancer.

cancer biology↗