Biology subjects

Gorgoulis, V. G.

Publications and source records attributed to Gorgoulis, V. G..

5 recordsLinked to original sources

bioRxiv2025

Immune cell senescence drives responsiveness to immunotherapy in melanoma

AbstractBackground: Immunotherapy has significantly improved cancer treatment. However, it is not effective in all cancer patients, rendering the need to further delineate the differences among responders and non-responders at the molecular and cellular level. Unresponsiveness to immunotherapy has been attributed to dysfunctional immune cell states such as T-cell exhaustion and anergy, whereas the contribution of cellular senescence remains elusive. Herein, we have investigated the role of immune cell senescence in the response to checkpoint inhibitors in melanomas where these immunotherapies are applied as a first line treatment. Methods: Two senescence detecting complementary approaches were utilized in a case control study we conducted. First, we implemented a senescence molecular signature we developed, termed "SeneVick" retrospectively in a single cell RNA-seq dataset from melanoma patients who received immunotherapy. Prior to this analysis, the signature was extensively validated in a variety of cell/tissue contexts, senescence types and species. Second, cellular senescence was assessed via an established experimental algorithmic approach in circulating immune cells of an analogous melanoma clinical cohort. Results: Melanoma patients who did not respond to immunotherapy exhibited increased cellular senescence in their CD8+ T-cells, CD4+ T-cells, B-cells and NK cells compared to responders. This phenomenon was independent of patients age and not an outcome of immunotherapy, in contrast to conventional anti-cancer treatments. Interestingly, alterations of cell-cell interactions among the immune sub-populations in non-responders compared to responders were identified, suggesting the involvement of immune cell senescence in defective immune responses and treatment failure. Conclusion: Overall, our findings support cellular senescence of the immune cell compartment within the TME, as a potent determinant of the response to immunotherapy and pave the way for strategies targeting immune cell senescence, as promising approaches to improve the outcome of such interventions.

immunology↗

bioRxiv2023

Senescent cells in Giant Cell Arteritis have inflammatory phenotype participating in tissue injury via IL-6 dependent pathways

ObjectivesAge is the strongest risk factor of Giant Cell Arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multi-marker algorithm in tissue artery biopsies (TABs) of GCA patients. MethodsSeventy five positive TABs from GCA patients and 22 negative from patients with Polymyalgia Rheumatica (PMR) were retrospectively retrieved and analyzed. Senescent cells and their histologic origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype (SASP) by triple co-staining. GCA or PMR artery culture supernatants were applied to primary skin fibroblasts with or without IL-6 blocking agent to explore the induction of IL-6 associated cellular senescence. ResultsSenescent cells were mainly present in GCA arteries at higher proportion compared to PMR (9.50% vs 2.66% respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts and macrophages while MMP-9 by fibroblasts only. IL-6 positive senescent cells were associated with the extension of vascular inflammation (adventitial limited disease vs transmural inflammation: 10.02% vs 4.37% respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6 blockade. ConclusionsSenescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk. These findings might suggest a potential implication in disease pathogenesis by perpetuating inflammation and affecting vascular remodeling via IL-6 dependent mechanisms.

cell biology↗

bioRxiv2021

53BP1 mediated recruitment of RASSF1A at ribosomal DNA breaks facilitates local ATM signal amplification

DNA lesions occur across the genome and constitute a threat to cell viability; however, damage at specific genomic loci has a disproportionally greater impact on the overall genome stability. The ribosomal RNA gene repeats (rDNA) are emerging fragile sites due to repetitive nature, clustering and high transcriptional activity. Notably, recent progress in understanding how the rDNA damage response is organized has highlighted the key role of adaptor proteins in the response. Here we identify that the scaffold and tumor suppressor, RASSF1A is recruited at sites of damage and particularly enriched at rDNA breaks. Employing targeted nucleolar DNA damage, we find that RASSF1A recruitment requires ATM activity and depends on the 53BP1. At sites of damage RASSF1A facilitates local ATM signal establishment and rDNA break repair. RASSF1A silencing, a common epigenetic event during malignant transformation, results in persistent breaks, rDNA copy number alterations and decreased cell viability. Moreover, meta-analysis of a lung adenocarcinoma cohort showed that epigenetic silencing of the scaffold leads in rDNA copy number discrepancies. Overall, we present evidence that RASSF1A acts as a DNA repair factor and offer mechanistic insight in how the nucleolar DNA damage response is organized.

cell biology↗

bioRxiv2020

Genomic instability is an early event driving chromatin reorganization and escape from oncogene-induced senescence

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not timely removed via immune surveillance, senescent cells will also present a detrimental side. Although this has mostly been attributed to the senescence-associated-secretory-phenotype (SASP) of these cells, we recently proposed that "escape" from the senescent state represents another unfavorable outcome. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion, which harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and for driving cell cycle re-entry and malignant transformation. In summary, we now provide strong evidence in support of genomic instability underlying "escape" from oncogene-induced senescence. HIGHLIGHTSO_LIOncogene driven error-prone repair produces early genetic lesions allowing escape from senescence C_LIO_LICells escaping oncogene-induced senescence display mutational signatures observed in cancer patients C_LIO_LIA single recurrent inversion harboring a circadian TF gene suffices for bypassing oncogene-induced senescence C_LIO_LIChromatin loop and compartment remodeling support the "escape" transcriptional program C_LI

cell biology↗

bioRxiv2020

A Machine Learning approach for assessing drug development risk

Characterizing drug development risk - the probability that a drug will eventually receive regulatory approval - has been notoriously hard given the complexities of drug biology and clinical trials. This often leads to an inefficient allocation of resources, and an overall reduction in R&D productivity. We propose a Machine Learning (ML) approach that provides a more accurate and unbiased estimate of drug development risk than traditional models.

bioinformatics↗