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Targeting non-junctional Claudin-1 with monoclonal antibodies to treat hepatocellular carcinoma [scRNA-seq]

ABSTRACT: Abstract: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Despite new treatment approvals, treatment response and prognosis of patients with advanced HCC remains poor. Claudin-1 (CLDN1) is a membrane protein expressed in tight junctions but also non-junctionally at the basolateral membrane of hepatocytes. While the function of CLDN1 within tight junctions is well characterized, the role of non-junctional (NJ) CLDN1 in HCC remains unexplored. Here we show that targeting NJ-CLDN1 with a humanized monoclonal antibody (mAb) suppresses tumor growth in different pre-clinical models. Mechanistic studies including single cell RNA sequencing of multicellular patient tumorspheres suggest that non-junctional CLDN1 regulates tumor stemness, metabolism and oncogenic signaling with impact on the tumor immune microenvironment. Our results provide the rationale for targeting NJ-CLDN1 in HCC and pave the way to novel therapeutic interventions with NJ-CLDN1 mAbs aimed at improving the limited efficacy of current therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196392 | GEO | 2025/01/29

REPOSITORIES: GEO

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Project description:The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. Transcriptome analysis revealed a global down-regulation of physiological AJC gene expression in the SAE of healthy smokers (n=53) compared to healthy nonsmokers (n=59), an observation associated with changes in molecular pathways regulating epithelial differentiation such as PTEN signaling and accompanied by induction of cancer-related AJC genes. Genome-wide co-expression analysis identified a smoking-sensitive AJC transcriptional network. The overall expression of AJC-associated genes was further decreased in COPD smokers (n=23). Exposure of human airway epithelial cells to cigarette smoke extract in vitro resulted in down-regulation of several AJC-related genes, accompanied by decreased transepithelial resistance. Thus, cigarette smoking alters the AJC gene expression architecture in the human airway epithelium, providing a molecular basis for the dysregulation of airway epithelial barrier function during the development of smoking-induced lung disease. The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. In this study, microarray analysis of the SAE obtained from 53 healthy nonsmokers, 59 healthy smokers, and 23 smokers with COPD was performed to determine physiological AJC gene expression architecture in the SAE and its modification by cigarette smoking and during the development of COPD.

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Targeting non-junctional Claudin-1 with monoclonal antibodies to treat hepatocellular carcinoma [scRNA-seq]

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