Biology subjects

Licursi, V.

Publications and source records attributed to Licursi, V..

3 recordsLinked to original sources

bioRxiv2023

Dbx2, an aging-related homeobox gene, inhibits the proliferation of adult neural progenitors

The subventricular zone (SVZ) of the adult mouse brain contains quiescent neural stem cells, which can be activated (aNSCs) to generate transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. Neurogenesis declines during aging, as the aged SVZ niche causes transcriptomic changes that promote NSC quiescence and decrease proliferating neural/stem progenitor cells (NSPCs). The transcription factors mediating these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in aged SVZ NSPCs and inhibits NSPC culture growth. Here, we report that Dbx2 is repressed by Epidermal Growth Factor Receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. We show that Dbx2 inhibits NSPC proliferation by hindering the G2/M transition and elucidate the transcriptomic networks modulated by Dbx2, highlighting its role in the downregulation of the cell cycle molecular pathways. Accordingly, Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a molecular node relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome.

developmental biology↗

bioRxiv2021

GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in early-stage colorectal tumors and predict poor clinical outcome.

Tumor contexture has emerged as a major prognostic determinant and tumor infiltrating CD8+ T cells have been associated with a better prognosis in several solid tumors, including early-stage colorectal cancer (CRC). However, the tumor immune infiltrate is highly heterogeneous and understanding how the interplay between different immune cell compartments impacts on the clinical outcome is still in its infancy. Here, we describe in a prospective cohort a novel CD8+ T effector memory population, which is characterized by high levels of Granzyme K (GZMKhigh CD8+ TEM) and is correlated with CD15high tumor infiltrating neutrophils. We provide both in vitro and in vivo evidence of the role of stromal cell-derived factor 1 (CXCL12/SDF-1) in driving functional changes on neutrophils at the tumor site, promoting their retention and increasing the crosstalk with CD8+ T cells. Mechanistically, as a consequence of the interaction with neutrophils, CD8+ T cells are skewed towards a CD8+ TEM phenotype and produce high levels of GZMK, which in turn decreases E-cadherin pathway. The correlations of GZMKhigh CD8+ TEM and neutrophils with both tumor progression in mice and early relapse in CRC patients demonstrate the role of GZMKhigh CD8+ TEM in promoting malignancy. Indeed, a gene signature defining GZMKhigh CD8+ TEM was associated with worse prognosis on a larger independent cohort of CRC patients and a similar analysis was extended to lung cancer (TCGA). Overall, our results highlight the emergence of GZMKhigh CD8+ TEM in early-stage CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics.

immunology↗

bioRxiv2019

Integrated transcriptomic correlation network analysis identifies COPD molecular determinants

Chronic obstructive pulmonary disease (COPD) is a heterogeneous and complex syndrome. Network-based analysis implemented by SWIM software can be exploited to identify key molecular switches - called \"switch genes\" - for disease. Genes contributing to common biological processes or define given cell types are frequently co-regulated and co-expressed, giving rise to expression network modules. Consistently, we found that the COPD correlation network built by SWIM consists of three well-characterized modules: one populated by switch genes, all up-regulated in COPD cases and related to the regulation of immune response, inflammatory response, and hypoxia (like TIMP1, HIF1A, SYK, LY96, BLNK and PRDX4); one populated by well-recognized immune signature genes, all up-regulated in COPD cases; one where the GWAS genes AGER and CAVIN1 are the most representative module genes, both down-regulated in COPD cases. Interestingly, 70% of AGER negative interactors are switch genes including PRDX4, whose activation strongly correlates with the activation of known COPD GWAS interactors SERPINE2, CD79A, and POUF2AF1. These results suggest that SWIM analysis can identify key network modules related to complex diseases like COPD.

bioinformatics↗