Biology subjects

Duran, D.

Publications and source records attributed to Duran, D..

4 recordsLinked to original sources

bioRxiv2026

TLR2-mediated microbial sensing by intestinal stem cells coordinates epithelial antimicrobial defense.

Intestinal regeneration and host defense require adaptation to environmental cues, but the mechanisms underlying this coordination remain unclear. We show that intestinal Lgr5 stem cells act as luminal sensors via apically localized Toll-like receptor 2 (TLR2), enabling direct detection of microbiota-derived signals. We identify apical TLR2 activation as a mechanism of luminal sensing in adult stem cells and show that it controls epithelial differentiation, antimicrobial peptide production, and crypt organization, with a particularly strong influence on Paneth cell maturation. Genetic ablation of constitutive, epithelial, or stem cell-specific TLR2 disrupts these processes, leading to impaired antimicrobial defense and altered epithelial composition. Using germ-free mice and human intestinal organoids, we demonstrate that this pathway is microbiota-dependent and evolutionarily conserved, respectively. These findings support a model in which stem cells act as active integrators of environmental information and suggest a broader principle by which barrier tissues couple microbial sensing to regeneration and host protection.

immunology↗

bioRxiv2024

Immortalized Intestinal Telocytes - A Stem Cell Niche In Vitro

Telocytes, a distinct type of mesenchymal cell, have recently emerged as crucial components of the intestinal stem cell niche, primarily by providing essential Wnt proteins that drive stem cell function. However, their detailed biology and the specific mechanisms by which they regulate stem cell activity remain largely unexplored. Here, we established an immortalized intestinal telocyte cell line that retains the key cellular and molecular characteristics of native telocytes. Remarkably, this cell line, unlike telocyte-depleted immortalized mesenchyme, supports the growth of both mouse and human organoids in co-culture without the need for external factor supplementation. These findings indicate that telocytes are not only essential but are also sufficient to maintain stem cell activity. This immortalized telocyte line provides a valuable source of factors that support stem cell activity in vitro, offering a powerful tool for advancing our understanding of telocyte biology and the reciprocal communication between stem cells and their niche.

cell biology↗

bioRxiv2024

AVJ16 inhibits the RNA binding protein IGF2BP1 in lung adenocarcinomas and prevents tumor growth in mice

IGF2BP1 is an oncofoetal RNA binding protein that is expressed in many tumors. We have recently described a small molecule inhibitor of IGF2BP1, termed AVJ16, that prevents binding of the protein to its RNA targets by directly associating with the protein. Here, using a multi-omics approach, we have analyzed the effects of this inhibition on RNA binding, RNA expression, and protein expression. AVJ16 treatment downregulates RNAs encoding members of several pro-oncogenic signaling pathways, including Hedgehog, Wnt, and PI3K-Akt, and there is a strong correlation between IGF2BP1 RNA binding, RNA expression, and protein expression. AVJ16 treatment of lung adenocarcinoma (LUAD) cells in culture causes a strong reduction in proliferation, colony formation, invasion, and spheroid growth while enhancing apoptosis and cell death. All of these effects are limited to cells expressing IGF2BP1. LUAD cells treated with AVJ16 show a pronounced reduction in vital dye efflux, often correlated with enhanced chemosensitivity. In syngeneic LUAD xenografts in mice, IP injection of AVJ16 prevents tumor growth, and incubation with AVJ16 induces cell death in human organoids derived from IGF2BP1-expressing LUADs but not from healthy lung tissue. These results suggest that AVJ16 is a promising candidate for mono- and/or adjuvant therapy directed against tumors expressing IGF2BP1.

cancer biology↗

bioRxiv2023

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

genomics↗