Biology subjects

Cruz-Acuna, R.

Publications and source records attributed to Cruz-Acuna, R..

3 recordsLinked to original sources

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↗

bioRxiv2022

Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma 3D organoids and identify matrix-activated therapeutic targets

Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying pro-tumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevant in vitro 3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis. Here, we describe a modular, tumor ECM-mimetic hydrogel platform with tunable mechanical properties, defined presentation of cell-adhesive ligands, and protease-dependent degradation that supports robust in vitro growth and expansion of patient-derived EAC 3D organoids (EAC PDOs). Hydrogel mechanical properties control EAC PDO formation, growth, proliferation and activation of tumor-associated pathways that elicit stem-like properties in the cancer cells, as highlighted through in vitro and in vivo environments. We also demonstrate that the engineered hydrogel serves as a platform to identify potential therapeutic targets to disrupt the contribution of pro-tumorigenic increased matrix mechanics in EAC. Together, these studies show that an engineered PDO culture platform can be used to inform the development of therapeutics that target ECM stiffness in EAC.

bioengineering↗

bioRxiv2021

Single cell transcriptomic analysis reveals cellular diversity of murine esophageal epithelium and age-associated mitochondrial dysfunction

Stratified squamous epithelium of the esophagus is comprised of basal keratinocytes that execute a terminal differentiation program in overlying suprabasal and superficial cell layers. Although morphologic progression coupled with expression of specific molecular markers has been characterized along the esophageal epithelial differentiation gradient, the molecular heterogeneity within the cell types along this trajectory has yet to be classified at the level of single cell resolution. To explore the molecular characteristics of esophageal keratinocytes along the squamous differentiation continuum, we performed single cell RNA-Sequencing transcriptomic profiling of 7,972 cells from murine esophageal epithelial sheets. We identified 8 distinct cell clusters in esophageal epithelium, unveiling an unexpected level of diversity, particularly among basal cells. We further mapped the cellular pathways and lineage trajectories within basal, suprabasal, and superficial clusters as well as within the heterogeneous basal cell populations, providing a comprehensive molecular view of esophageal epithelial cells in the context of squamous differentiation. Finally, we explored the impact of tissue aging upon esophageal epithelial cell clusters and demonstrated that mitochondrial dysfunction is a feature of aging in normal esophageal epithelium. These studies provide an unparalleled molecular perspective on murine esophageal keratinocytes that will serve as a valuable resource for dissecting cell type-specific roles in esophageal biology under conditions of homeostasis, aging, and tissue pathology.

molecular biology↗