Biology subjects

Salvador, B.

Publications and source records attributed to Salvador, B..

2 recordsLinked to original sources

bioRxiv2023

Anti-inflammatory immunomodulation for the treatment of Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) is a rare disease where the diaphragm does not develop properly altering lung development with no established therapy. We have analyzed the effect of anti-inflammatory immunomodulators that influence macrophage activation in animal CDH models. In the widely-used nitrofen-induced model of CDH in pregnant rats, administration of a single dose of atypical Toll-like Receptors TLR2/4 dual ligands (CS1 and CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73 % of the fetuses, repaired the lesion with complete diaphragm closure. Moreover, they also improve pulmonary hypoplasia and vessel hypertrophy, enhancing pulmonary maturity of fetuses. CS1 treatment also rescued the CDH phenotype in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Only 1 out 11 mutant embryos showed CDH after CS1 administration, whereas CDH prevalence was 70% in untreated mutant embryos. Mechanistically, CS1 stimulated the infiltration of repairing M2 macrophages (CD206+ and Arg1+) into the damaged diaphragm and reduced T cell infiltration. Alteration in retinoic acid pathways a have been also implicated in the etiology of CDH. TLR2/4 dual ligands also induced retinol pathway genes, including RBP1, RALDH2, RAR and RAR{beta}, in the affected lungs and the diaphragm and in macrophages in vitro. The present results place atypical TLR2/4 ligands as a promising solution for CDH, where the own immune system of the fetus is responsible for repairing the hernia/damage in the diaphragm, ensuring the correct positioning and development of all organs.

immunology↗

bioRxiv2020

KRASG12D mutant cells are outcompeted by wild type neighbours in adult pancreas in an EPHA2-dependent manner.

As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbours for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that prior to being cleared, KrasG12D cells lose cell volume, segregate from normal cells and decrease E-cadherin-based cell-cell adhesions with normal neighbours. We identify EphA2 receptor is an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells no longer segregate, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. Retention of KRasG12D cells leads to an increased burden of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumour suppressor in pancreatic cancer.

cell biology↗