Biology subjects

Dominguez, A.

Publications and source records attributed to Dominguez, A..

4 recordsLinked to original sources

bioRxiv2025

NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress

Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor permissive genetic mutations, nature of cellular origin and microenvironmental stress. In this study, using primary human pancreatic acinar 3D organoids, we performed CRISPR knockout screen targeting 199 previously underappreciated potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidates, with NF2 emerging as the top target. Functional validation confirmed that loss of NF2 promotes the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 inactivation was found to enhance PDAC cell fitness under nutrient starvation. This adaptation not only reinforces the oncogenic state but also confers therapeutical resistance. Additionally, we found that NF2 loss is associated with the fibroblast heterogeneity and cancer-stroma communications in tumor evolution. These findings establish NF2 as a critical tumor suppressor in PDAC and uncover its role in mediating nutrient adaptation and drug resistance. Importantly, this study provides new insights into drug resistance mechanisms and potential therapeutic targets in PDAC.

cancer biology↗

bioRxiv2025

Targeted Tumor Microenvironment Delivery of Floxuridine Prodrug via Soluble Silica Nanoparticles in Malignant Melanoma as a Model for Aggressive Cancer Treatment

Malignant melanoma presents a significant challenge in oncology due to its aggressive nature and high metastatic potential. Conventional systemic treatments often fail to effectively reach tumor sites, limiting their therapeutic impact. This study introduces a groundbreaking triple-strategy approach for treating malignant melanoma. We developed a novel prodrug, an oligonucleotide, comprising 10 units of Floxuridine (5-fluoro-2-deoxyuridine) (FdU) nucleoside antimetabolites, to enhance half-life and reduce rapid metabolism. Encapsulated in soluble colloidal silica nanoparticles, this compound is protected and directed towards tumor neovasculature precursor endothelial cell receptors, ensuring local delivery. The strategy focuses on releasing the prodrug in the tumor microenvironment, aiming to eradicate both melanoma cells and their supportive structures. Efficacy was demonstrated in cell culture studies and preclinical models of malignant melanoma, showing a remarkable 50% reduction in tumor size after just three intravenous treatments. These findings underscore the transformative potential of targeting endothelial cell membrane proteins for drug delivery. Our study paves the way for innovative targeted therapies, promising significant advancements in treatment strategies and improved outcomes for patients with metastatic cancers. Key PointsO_LITriple-strategy for treating melanoma: FdU10 prodrug, silica nanoparticle and targeted delivery. C_LIO_LIOligonucleotide prodrug (Floxuridine units) enhances half-life and reduces metabolism. C_LIO_LISoluble silica nanoparticles protect therapeutic FdU10 from nucleases and decorated with protein ligands are directed to tumor neovasculature endothelial cells. C_LIO_LISignificant 50% tumor reduction in preclinical melanoma models after systemic administration with targeted therapies. C_LI

bioengineering↗

bioRxiv2025

TERT prevents obesity-induced metabolic disorders by promoting adipose stem cell expansion and differentiation

Obesity is linked to limited adipose tissue (AT) remodeling capacity, leading to hypertrophic adipocytes, senescence, and inflammation. We used a mouse model expressing mTert (p21+/Tert) from the Cdkn1a locus to investigate the role of mTERT in obesity-induced metabolic disorders. Conditional expression of mTERT reduces metabolic disorders associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We show that ASPC expansion and differentiation are promoted in p21+/Tert obese mice, thereby reducing metabolic disorders. We further report that mTERT remodels the landscape of macrophages in AT of obese mice. Strikingly, inactivation of mTERT catalytic activity in p21+/Tert (p21+/TertCi) mice suppresses the promotion of adipocyte formation, but neither affects attenuation of senescence nor macrophage remodeling. These results highlight mTERTs canonical and non-canonical functions in reducing obesity-associated metabolic disorders. Conditional expression of TERT thus appears as a potential therapeutic option for obesity.

physiology↗

bioRxiv2018

Reversible inhibition of specific transcription factor-DNA interactions using CRISPR

The control of gene expression by transcription factor binding sites frequently determines phenotype. However, it has been difficult to assay the function of single transcription factor binding sites within larger transcription networks. Here, we developed such a method by using deactivated Cas9 to disrupt binding to specific sites on the genome. Since CRISPR guide RNAs are longer than transcription factor binding sites, flanking sequence can be used to target specific sites. Targeting deactivated Cas9 to a specific Oct4 binding site in the Nanog promoter blocked Oct4 binding, reduced Nanog expression, and slowed division. Multiple guide RNAs allows simultaneous inhibition of multiple binding sites and conditionally-destabilized dCas9 allows rapid reversibility. The method is a novel high-throughput approach to systematically interrogate cis-regulatory function within complex regulatory networks.

molecular biology↗