Biology subjects

Gabre, J.

Publications and source records attributed to Gabre, J..

4 recordsLinked to original sources

bioRxiv2025

STAT3 regulates basal cell identity and morphogenesis during early esophageal development

The transcription factor STAT3 plays broad roles in epithelial biology, yet its function in human esophageal development remains undefined. Using 2D and 3D human induced pluripotent stem cell (hiPSC)-derived platforms, we investigated how STAT3 regulates esophageal epithelial differentiation. We find that STAT3 is dispensable for definitive endoderm and anterior foregut endoderm specification but becomes essential during the transition to esophageal progenitor cells (EPCs). Inhibition of STAT3, via CRISPR-mediated knockout or siRNA, impairs the expression of key EPC and differentiation markers, including TP63, and disrupts 3D organoid formation. These defects are accompanied by reduced epithelial proliferation. Notably, STAT3 is highly expressed in human fetal esophageal tissues and hiPSC-derived organoids, while its deletion in the developing mouse esophagus does not affect epithelial architecture, highlighting species-specific differences. Together, these findings identify STAT3 as a critical determinant of basal cell identity and epithelial morphogenesis, revealing a developmental checkpoint in early human esophageal lineage commitment.

developmental biology↗

bioRxiv2025

Single-Cell RNA Sequencing and Inferred Protein Activity Analysis Reveal a Distinct Tumor Phenotype in Early-Onset Colorectal Cancer Patients

Colorectal cancer (CRC) diagnosed before age 50 years (early-onset CRC, EO-CRC) is rising at an alarming rate, yet its molecular and microenvironmental drivers remain poorly understood. EO-CRC is highly heterogeneous, and while subtle differences from late-onset CRC (LO-CRC) have been reported, their full extent remains unresolved due to the limited scope of previous studies. Here, we integrate public data with in-house clinical samples profiled by single-cell RNA sequencing (scRNA-seq) and multiplex immunofluorescence (mIF) to compare EO-CRC and LO-CRC. Additionally, we employ gene regulatory network-based protein activity inference (VIPER), enabling a more precise characterization of key regulatory proteins driving tumor-stroma interactions. Our analysis reveals that EO-CRC and LO-CRC have a largely similar immune composition, challenging previous reports of an "immune-cold" phenotype in EO-CRC. However, we identify distinct stromal differences, including a significant enrichment of fibroblasts in EO-CRC. Notably, we define a previously unrecognized epithelial subpopulation in EO-CRC, marked by high expression of toll-like receptor 4 (TLR4) and C-C chemokine receptor type 5 (CCR5)--key mediators of inflammation-driven tumor progression and fibroblast recruitment. These findings suggest that EO-CRC may be driven by a tumor-intrinsic inflammatory phenotype with enhanced stromagenesis, providing new insights into potential mechanisms underlying its increasing incidence in young adults.

cancer biology↗

bioRxiv2024

EPHA2 Regulates SOX2 during Esophageal Development

The human esophagus, derived from the anterior foregut endoderm, requires proper dorsal-ventral patterning for development. The transcription factor SOX2, crucial in this process, when dysregulated, leads to congenital esophageal abnormalities. EPHA2, a receptor tyrosine kinase, is vital in various developmental processes and cancer models, where it activates SOX2. This study demonstrates that EPHA2 regulates SOX2 expression during esophageal development using human iPSCs and iPSC-derived human esophageal organoids (HEO). Inhibition of EPHA2 decreased iPSC-derived HEO formation and SOX2 expression. These findings provide evidence of EPHA2 as being a key regulator of SOX2 signaling in early esophageal development. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/617209v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@16b8a8aorg.highwire.dtl.DTLVardef@1548672org.highwire.dtl.DTLVardef@46e28corg.highwire.dtl.DTLVardef@1c35578_HPS_FORMAT_FIGEXP M_FIG SFD: Serum-Free Differentiation media; EPC: esophageal progenitor cells; HEO: human esophageal organoids Created with BioRender.com C_FIG HighlightsO_LISOX2 is crucial for proper esophageal development. C_LIO_LIEPHA2 is a receptor tyrosine kinase involved in various developmental processes. C_LIO_LIEPHA2 activates SOX2. C_LIO_LIInhibition of EPHA2 decreased SOX2 expression and human esophageal organoid formation. C_LI

developmental biology↗

bioRxiv2023

Preclinical exploration of the DNA Damage Response pathway using the interactive neuroblastoma cell line explorer CLEAN.

Neuroblastoma (NB) is the most common cancer in infancy with an urgent need for more efficient targeted therapies. The development of novel (combinatorial) treatment strategies relies on extensive explorations of signaling perturbations in neuroblastoma cell lines, using RNA-Seq or other high throughput technologies (e.g., phosphoproteomics). This typically requires dedicated bioinformatics support, which is not always available. Additionally, while data from published studies are highly valuable and raw data (e.g., fastq files) are nowadays released in public repositories, data processing is time-consuming and again difficult without bioinformatics support. To facilitate NB research, more user-friendly and immediately accessible platforms are needed to explore newly generated as well as existing high throughput data. To make this possible, we developed an interactive data centralization and visualization web application, called CLEAN (the Cell Line Explorer web Application of Neuroblastoma data; https://ccgg.ugent.be/shiny/clean/). By focusing on the regulation of the DNA damage response, a therapeutic target of major interest in neuroblastoma, we demonstrate how CLEAN can be used to gain novel mechanistic insights and identify putative drug targets in neuroblastoma.

cancer biology↗