Biology subjects

Athineos, D.

Publications and source records attributed to Athineos, D..

6 recordsLinked to original sources

bioRxiv2026

Cholesterol and p53 promote senescence and systemic fibrosis in metabolic dysfunction-associated steatohepatitis

Background & aims: TP53 (p53) coordinates diverse cellular stress response programmes including pro-survival activities, senescence, and cell death. During tissue damage, p53 can shape both the local cellular response to injury, including the fibrotic response, and influence distal organ biology. Fibrosis in the liver is a major driver of hepatocellular carcinoma (HCC) risk within metabolic dysfunction-associated steatohepatitis (MASH). It is also an important determinant of dysfunction in multiple distal tissues including the kidneys, lungs, and heart. Despite significant clinical burden, our understanding of the molecular determinants of fibrotic MASH and its relationship to multiorgan fibrosis remain incomplete. Here, we investigate local and systemic effects of hepatocellular p53 activity and cholesterol during MASH development, with implications for disease prevention. Methods: This study utilised a genetic model of stabilised p53, diet-induced MASH models with varying cholesterol compositions, and an in vitro obesogenic system to investigate p53 activity during liver disease development. Non-invasive imaging and histopathological analyses were employed to monitor p53 activity, MASH, and multiorgan fibrosis in vivo. Complementary approaches, including in vitro human multicomponent liver spheroids, cytokine arrays, and analyses of human MASH transcriptomic and proteomic datasets, were used to examine molecular drivers and patient relevance. Results: Using an inducible mouse model of MDM2 E3 ubiquitin ligase deficiency to stabilise p53, we report that hepatocellular MDM2 E3 loss results in progressive fibrotic damage, robust hepatocellular expression of the p53 target gene CDKN1A/p21 (p21),and induces p21 and fibrosis in the kidneys of male mice in a sex-specific manner. In diet-induced MASH, we observe cholesterol and p53-dependent development of liver fibrosis, high expression of hepatocellular p21, and induction of p21 and fibrosis in the kidneys of male mice-reminiscent of features observed in MDM2 E3-deficient mice. We also observe fibrosis in the lungs and heart of male MASH mice. Both a cholesterol-free obesogenic diet and liver-specific loss of p53 mitigate hepatic fibrosis and systemic induction of p21 and fibrosis. Mechanistically, p53 induces hepatic expression of senescence-associated secretory phenotype (SASP) factors, including GDF15, in vivo. A human multicomponent LiverACE spheroid model showed a concordant trend towards increased GDF15 protein abundance under steatotic stress, while in humans, elevated circulating GDF15 levels in advanced MASH correlate with increased TNFRSF1A and EPHA2, circulating markers linked to kidney injury. Conclusions: Our work identifies undue p53 activity within the liver as a driver of multiorgan fibrosis in a sex-specific manner, affecting male but not female mice. We implicate cholesterol in promoting this pro-fibrotic environment in vivo and highlight circulating factors that could identify at-risk patients for multiorgan fibrosis in MASH.

cancer biology↗

bioRxiv2025

Runx1 and Runx2 act in concert to suppress Wnt/β-catenin-driven mammary tumourigenesis

The genes encoding transcription factor RUNX1 and its binding partner CBFB have been reported to be mutated in human breast cancer. Here, we provide evidence that Runx1 loss of function results in accelerated disease onset and tumour development in mouse models of breast cancer, in keeping with a tumour suppressor role for RUNX1 in this disease setting. Combined deletion of Runx1 and the related family member Runx2 resulted in mammary epithelial cells becoming exquisitely sensitive to WNT-driven transformation, with the emergence of multiple tumours early in life. Clonogenic assays indicated that Runx1 ablation induced a stem cell like phenotype in mammary epithelial cells, whilst transcriptome analysis demonstrated activation of multiple oncogenic pathways, especially when Runx2 was co- deleted. Interestingly, altered Runx expression in the mammary epithelium also drove profound alterations in the tumour microenvironment, impacting the immune landscape. These results highlight that Runx1 restricts some forms of breast cancer and inhibits the full oncogenic potential of aberrant WNT signalling. Loss of Runx2 itself did not result in tumour promotion, yet the dramatic effects of combined Runx1 and Runx2 loss suggest that Runx2 can substitute for Runx1 in dampening the oncogenic effects of WNT signalling.

cancer biology↗

bioRxiv2024

p53 and TIGAR promote redox control to protect against metabolic dysfunction-associated steatohepatitis

TP53 is a potent tumour suppressor that coordinates diverse stress response programmes within the cell. The activity of p53 is frequently context and cell type-dependent, and ranges from pro-survival activities, including the implementation of transient cell cycle arrest and metabolic rewiring, through to cell death. In addition to tumour suppressor functions, p53 also has established roles in the pathological response to stress that occurs during tissue damage and repair, including within the liver. Metabolic dysfunction-associated steatohepatitis (MASH) is a major driver of hepatocellular carcinoma (HCC), but our understanding of the molecular determinants of MASH development remains incomplete. Here, using a p53 reporter mouse, we report early and sustained activation of hepatic p53 in response to an obesogenic high fat and high sugar diet. In this context, liver-specific loss of p53 accelerates the progression of benign fatty liver disease to MASH that is characterised by high levels of reactive oxygen species (ROS), extensive fibrosis, and chronic inflammation. Using an in vitro culture system, we show that p53 functions to control ROS and protect against the development of MASH, in part through induction of the antioxidant gene TP53-induced glycolysis and apoptosis regulator (TIGAR). Our work demonstrates an important role for the p53-TIGAR axis in protecting against MASH, and identifies redox control as an essential barrier against liver disease progression.

cancer biology↗

bioRxiv2023

Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function

Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we unveil a mechanism of cell-cell communication between CAFs with myofibroblast phenotype and endothelial cells (ECs) based on intercellular protein transfer through extracellular vesicles (EVs). CAFs transfer proteins to ECs, including plasma membrane receptors, which we have identified by using mass spectrometry- based proteomics. Using THY1 as an example of transferred plasma membrane-bound protein, we show that CAF-derived proteins can influence how ECs interact with other cell types. Here, we show that CAFs produce high amounts of matrix-bound EVs that have a key role in protein transfer. Hence, our work paves the way for further studies to understand how CAF-derived matrix-bound EVs influence tumor pathology by regulating functions of neighboring cancer, stromal and immune cells. One sentence summaryCAFs with a myofibroblastic-like phenotype transfer proteins to ECs, including plasma membrane receptors, through matrix-bound EVs

cancer biology↗

bioRxiv2020

Impact of formate supplementation on body weight and plasma amino acids

Current nutritional recommendations are focused on energy, fat, carbohydrate, protein and vitamins. Less attention has been paid to the nutritional demand of one-carbon units for nucleotide and methionine synthesis. Here we investigate the impact of sodium formate supplementation as a nutritional intervention to increase the dietary intake of one-carbon units. A cohort of six female and six male mice received 125 mM sodium formate in the drinking water for three months. A control group of another six female and six male mice was also followed up for the same period of time. Tail vein blood samples were collected once a month and profiled with a haematology Analyser. At the end of the study blood and tissues were collected for metabolomics analysis and immune cell sorting. Formate supplementation has no significant physiological effect on male mice. Formate supplementation has no significant effect on the immune cell counts during the intervention or at the end of the study in either gender. In female mice however, the body weight and spleen wet-weight were significantly increased by formate supplementation, while the blood plasma levels of amino acids were decreased. Formate supplementation also increased the frequency of probiotic bacteria in the stools of female mice. We conclude that formate supplementation induces physiological changes in female mice.

biochemistry↗

bioRxiv2019

Formate induces a metabolic switch in nucleotide and energy metabolism

Formate is a precursor for the de novo synthesis of purine and deoxythymidine nucleotides. Formate also interacts with energy metabolism by promoting the synthesis of adenine nucleotides. Here we use theoretical modelling together with metabolomics analysis to investigate the link between formate, nucleotide and energy metabolism. We uncover that endogenous or exogenous formate induces a metabolic switch from low to high adenine nucleotide levels, increasing the rate of glycolysis and repressing the AMPK activity. Formate also induces an increase in the pyrimidine precursor orotate and the urea cycle intermediate argininosuccinate, in agreement with the ATP dependent activities of carbamoyl-phosphate and argininosuccinate synthetase. In vivo data for mouse and human cancers confirms the association between increased formate production, nucleotide and energy metabolism. Finally, the in vitro observations are recapitulated in mice following intraperitoneal injection of formate. We conclude that formate is a potent regulator of purine, pyrimidine and energy metabolism.

biochemistry↗