Biology subjects

Delgado-Bellido, D.

Publications and source records attributed to Delgado-Bellido, D..

3 recordsLinked to original sources

bioRxiv2026

EXO1 Facilitates MiDAS and Prevents Genome Instability and Cell Death in Ewing Sarcoma

Ewing sarcoma (EwS) is an aggressive malignancy driven by EWSR1::ETS fusions, predominantly EWSR1::FLI1. Previous efforts using both direct and indirect approaches to target these chimeric oncoproteins have yielded limited clinical benefit. Although EWSR1::FLI1 is a well-known source of replication stress and genome instability, targeting DNA damage response (DDR) factors that mitigate these effects remain poorly understood. Here, we identified a marked dependency of EwS cells on exonuclease 1 (EXO1). We demonstrate that EXO1 is essential for EwS cell survival and tumor growth, highlighting its potential as a novel therapeutic target. Intriguingly, we unveil that EXO1 loss impairs mitotic DNA synthesis (MiDAS), promoting EWSR1::FLI1-associated genome instability and cell death. Collectively, our results support the idea that targeting DDR factors, which counteract replication stress and/or DNA damage induced by fusion oncoproteins, represents a promising therapeutic option for EwS.

cancer biology↗

bioRxiv2023

EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism

Drug resistance is one of the major factors associated with poor outcome of cancer patients. Treatment of Ewing sarcoma (EwS), an aggressive neoplasm mainly affecting children, adolescents and young adults, is associated with therapy failure and tumor relapse in 30-80% of the cases. Thus, it supports the need to explore the mechanisms modulating drug activity. Here, we describe a novel mechanism of drug sensitivity based on the role of EWS::FLI1 in R-loop metabolism. Our results demonstrate that EWS::FLI1 promotes R-loop formation favoring the interaction between DHX9 and elongating RNA polymerase II. In addition, we discovered that EWS::FLI1 kidnaps DHX9 preventing the resolution of TOP1 poisoning-associated R-loops. Our findings indicate that R-loops accumulation promotes replicative stress, genome instability and cell sensitivity to SN-38. Collectively, these results uncover a novel mechanism behind EwS sensitivity to genotoxic agents, with relevant implications for EwS treatment.

cancer biology↗

bioRxiv2019

VE-PTP participates in vasculogenic mimicry by preventing autophagic degradation of VE-cadherin

Aberrant extra-vascular expression of VE-cadherin has been observed in metastasis associated with Vasculogenic Mimicry (VM); we have recently shown that in VM prone (VM+) tumor cells VE-cadherin is mainly in the form of pVE-cadherin in Y658 allowing an increased plasticity that potentiates VM development. As excessive VE-cadherin phosphorylation is regulated by the phosphatase VEPTP in endothelial cells in the current study we analysed its role in this aberrant phenotype in malignant tumor cells. We show that human malignant melanoma cells VM+, also express VE-PTP although at lower levels than endothelial cells. The complex VE-PTP/VE-Cadherin/p120-catenin act as a safeguard to prevent VE-cadherin degradation by autophagy. Indeed, silencing of VE-PTP results in complete degradation of VE-cadherin with the features of autophagy and increases the global p120 tyrosine phosphorylation status. In summary, we show that VE-PTP is involved in VM formation and disruption of VE-PTP/VE-Cadherin/p120 complex results in enhanced autophagy in aggressive VM+ cells.

cancer biology↗