Williams, B. J. | bioRxiv Science

bioRxiv2025

Adipocytes in tumour microenvironment promote chemoresistance in TNBC through oxysterols

ObjectiveTriple-negative breast cancer (TNBC) patients with excess adipose tissue experience poorer disease-free survival than those with a healthy body mass index. Adipocytes, abundant in mammary tissue, store and release cholesterol, which can be hydroxylated to form oxysterols. These cholesterol derivatives activate the liver X receptor (LXR) pathway. This study tested the hypothesis that adipocytes contribute to an imbalanced tumour-microenvironment by exposing cancer cells to elevated oxysterols, mimicking chemotherapy-exposure conditions and priming for chemoresistance. MethodsTumour tissue microarray from 148 TNBC patients was assessed using immunohistochemistry for expression of CH25H, CYP46A1, CYP27A1 and P-glycoprotein, and survival outcomes assessed. Gene expression was compared between tumours from patients and mouse models with high versus low adiposity. In vitro, cells of the tumour-microenvironment were evaluated for oxysterol content, secretion, expression of relevant enzymes, and their ability to induce P-glycoprotein expression and drug resistance in TNBC cells. ResultsIn patients, expression of oxysterol-synthesizing enzymes in stroma correlated with P-glycoprotein expression in cancer epithelial cells and was associated with shorter disease-free survival. Adipocytes conditioned media contained significantly higher oxysterols levels than that conditioned by other cell types and induced P-glycoprotein expression and drug resistance in MDA.MB.468 cells. Obese mice had elevated levels of P-glycoprotein in tumours compared to lean counterparts. ConclusionsAdipocytes secrete oxysterols that promote drug resistance in vitro and correlate with oxysterol:Pgp axis and survival in vivo. SignificanceThis study reveals a mechanism by which adipose tissue contributes to drug resistance in ER-negative breast cancers, identifying the oxysterol-Pgp axis as potential therapeutic target.

cancer biology↗

bioRxiv2018

Agmatine accumulation by Pseudomonas aeruginosa clinical isolates confers antibiotic tolerance and dampens host inflammation.

In the cystic fibrosis (CF) airways, Pseudomonas aeruginosa undergoes diverse physiological changes in response to inflammation, antibiotic pressure, oxidative stress and a dynamic bioavailable nutrient pool. These include loss-of-function mutations that result in reduced virulence, altered metabolism and other phenotypes that are thought to confer a selective advantage for long-term persistence. Recently, clinical isolates of P. aeruginosa that hyperproduce agmatine (decarboxylated arginine) were cultured from individuals with CF. Sputum concentrations of this metabolite were also shown to correlate with disease severity. This raised the question of whether agmatine accumulation might also confer a selective advantage for P. aeruginosa in vivo during chronic colonization of the lung. Here, we screened a library of P. aeruginosa CF clinical isolates and found that ~5% of subjects harbored isolates with an agmatine hyperproducing phenotype. Agmatine accumulation was a direct result of mutations in aguA, encoding the arginine deiminase that catalyzes the conversion of agmatine into various polyamines. We also found that agmatine hyperproducing isolates (aguA-) had increased tolerance to the cationic antibiotics gentamicin, tobramycin and colistin relative to their chromosomally complemented strains (aguA+). Finally, we revealed that agmatine diminishes IL-8 production by airway epithelial cells in response to bacterial infection, with a consequent decrease in neutrophil recruitment to the murine airways in an acute pneumonia model. These data highlight a potential new role for bacterial-derived agmatine that may have important consequences for the long-term persistence of P. aeruginosa in the CF airways.

microbiology↗