Biology subjects

O'Loghlen, A.

Publications and source records attributed to O'Loghlen, A..

4 recordsLinked to original sources

bioRxiv2025

p16INK4A expression induces paracrine senescence via small extracellular vesicles

Senescent cells are characterized by the expression of the cell cycle inhibitor and biomarker of aging, p16INK4A, and the capacity to modify the microenvironment through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in physiological and pathological conditions, including aging. In spite of this, fibroblasts ectopically expressing p16INK4A do not release a SASP nor communicate with the microenvironment. Here, we find that human primary fibroblasts expressing p16INK4A release more small extracellular vesicles (sEV) as part of the SASP than proliferating cells. In addition, we show that sEV isolated from p16INK4A cells are able to mediate paracrine senescence by inducing a growth arrest and DNA damage response in proliferating cells albeit not stimulating the expression of IL-8. Furthermore, we show the transmission of paracrine senescence via sEV is conserved in two cellular models of ageing: expression of progerin, mimicking an accelerated form of ageing, and inducing telomere shortening using a dominant negative mutant. Importantly, sEV isolated from fibroblasts derived from old donors also induce paracrine senescence in fibroblasts derived from young donors. In conclusion, our data indicate that sEV released by senescent and aging cells are an important mechanism of intercellular communication and could potentially explain tissue dysfunction in aging.

cell biology↗

bioRxiv2024

Plasma membrane transporter Progressive Ankylosis Protein Homolog (ANKH/Ankh) mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation and ageing

A considerable body of recent evidence supports citrate transport as a major regulator of organismal lifespan and healthspan. Citrate accumulates outside senescent cells in vitro and in vivo. However, the detailed mechanism of senescent cell extracellular citrate (EC) accumulation is not clear. We show here that EC is partially mediated by a newly described plasma membrane citrate transporter ANKH/SLC62A1 (progressive human ankylosis - ANKH) in senescent fibroblasts. Analogous to interleukin 6 (IL-6), EC and/or ANKH are regulated by telomere dysfunction, the p38 mitogen-activated kinase axis, transforming growth factor beta and p53, but in contrast not by steroids, sodium butyrate, or Ataxia Telangiectasia Mutated (ATM). ANKH was upregulated in other senescent cell types relevant to ageing but not keratinocytes. In contrast, EC and ANKH were inhibited in dividing and senescent fibroblasts by interleukin 1 (IL-1) in parallel with increased IL-6 secretion. Loss- and gain of function mutations of ANKH/Ank are associated with disease and interestingly, Ank is also downregulated in both aged mouse liver and brain tissues in parallel with increased senescence markers and several cytokines, suggesting that inflammatory cytokines could inhibit EC production in vivo. These data identify ANKH/Ank as a novel regulator of senescence-derived EC in both humans and mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/609895v3_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1eed642org.highwire.dtl.DTLVardef@1349040org.highwire.dtl.DTLVardef@1ea867aorg.highwire.dtl.DTLVardef@22d251_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

The coagulation factor IX (F9) loss of function prevents the cell cycle arrest induced by CDK4/6 inhibitors treatment

During this last decade the development of pro-senescence therapies has become an attractive strategy as cellular senescence acts as a barrier against tumour progression. In this context, CDK4/6 inhibitors induce senescence and have showed efficacy in reducing tumour growth in breast cancer patients. However, even though cancer cells are arrested after CDK4/6 inhibitor treatment, genes regulating senescence in this context are still unknown limiting their anti-tumour activity. Here, using a functional genome wide CRISPR/Cas9 genetic screen we found several genes that synergistically participate in the proliferation arrest induced by the CDK4/6 inhibitor, Palbociclib. We find that downregulation of the coagulation factor IX (F9) using sgRNA and shRNA prevents the cell cycle arrest and senescent-like phenotype induced in MCF7 breast tumour cells upon Palbociclib treatment. These results were confirmed using another breast cancer cell line and with an alternative CDK4/6 inhibitor, Abemaciclib, and further tested in a panel of 22 cancer cells. While F9 knockout reduces senescence, treatment with a recombinant F9 protein was sufficient to induce a cell cycle arrest and senescence-like state in MCF7 tumour cells. Besides, endogenous F9 is upregulated in different human primary cells cultures undergoing senescence. Importantly, bioinformatics analysis of cancer datasets suggest a role for F9 in human tumours. Altogether, these data collectively propose key genes involved in CDK4/6 inhibitors response that will be useful to design new therapeutic strategies in personalized medicine in order to increase their efficiency, stratify patients and avoid drug resistance.

cancer biology↗

bioRxiv2018

Exosomes are key regulators of non-cell autonomous communication in senescence

Senescence is a cellular phenotype characterized by an irreversible cell cycle arrest and the secretion of inflammatory proteins, denominated senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behavior of neighboring cells and altering the microenvironment; yet, until now this role has been mainly attributed to soluble factors. Here, we report that extracellular vesicles also alter the environment by transmitting the senescent phenotype to other cells via exosomes (extracellular vesicles of endocytic origin). A combination of functional assays, Cre-/oxP reporter systems, proteomic analysis and RNAi screens confirm that exosomes form part of the senescent secretome and mediate paracrine senescence via the activation of a non-canonical interferon (IFN) pathway. Altogether, we speculate that exosomes could be drivers of tissue degeneration both locally and systemically during aging and age- related disease.

cell biology↗