Biology subjects

Palladini, A.

Publications and source records attributed to Palladini, A..

5 recordsLinked to original sources

bioRxiv2026

Neuroendocrine-like/EMT dedifferentiation mediates resistance to EGFR inhibitors via the NRG1/HER3 axis

Patients with non-small cell lung cancer (NSCLC) carrying activating EGFR mutations typically respond favorably to third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib. Nevertheless, resistance almost inevitably emerges, ultimately limiting the durability of these treatments. We investigated non-genomic mechanisms enabling drug-tolerant persister cells to survive EGFR inhibition, likely co-opting compensatory HER3 activation, whose underlying mechanisms remain unclear. Using a combination of immortalized and patient-derived cellular models, together with single-cell RNA sequencing, we demonstrate that activation of EGFR/HER3 axis constitutes an early adaptive response to TKI exposure enriched in pulmonary alveolar type I and type II cancer cells. This response is driven by neuregulin-1 (NRG1), produced by stromal cells and by cancer cells undergoing NE-like/EMT dedifferentiation. Importantly, in vivo studies demonstrated that combining EGFR inhibition and NRG1 neutralization by monoclonal antibody successfully eradicated tumors. Together, these findings point to a therapeutic strategy to overcome TKI resistance in NSCLC through targeting HER3 signalling, its interplay with EGFR, and tumor microenvironment-derived cues.

cancer biology↗

bioRxiv2020

Obesity-associated lipidomic remodeling of the adrenal gland indicates an important role of the FADS2-arachidonic acid axis in adrenocortical hormone production

ObjectiveAdrenocortical hormone levels increase in obesity, potentially contributing to development of obesity-associated pathologies. Here we explored whether lipidomic remodeling of the adrenal gland could mediate altered adrenocortical steroidogenesis during obesity. MethodsLipidomic analysis was performed in adrenal glands using shotgun mass spectrometry (MS), and steroid profiling of sera by liquid chromatography tandem mass spectrometry (LC-MS/MS) from lean and obese mice. Gene expression analysis was performed in adrenal glands and adrenocortical cell populations. The role of Fatty Acid Desaturase 2 (FADS2) and arachidonic acid on steroid hormone production was studied in primary adrenal gland cell cultures. ResultsAdrenal glands of obese mice displayed a distinct lipidomic profile, encompassing longer and more unsaturated storage lipids and phospholipids compared to adrenal glands of lean mice. Arachidonoyl acyl chains were abundant in the adrenal gland phospholipidome and increased upon obesity. This was accompanied by increased Fads2 expression, the rate-limiting enzyme of arachidonic acid synthesis, and enhanced plasma adrenocortical hormone levels. Inhibition of FADS2 in primary adrenal gland cell cultures abolished steroidogenesis, which was restored by arachidonic acid supplementation. ConclusionsOur data suggest that the FADS2 - arachidonic acid axis regulates adrenocortical hormone synthesis, while alterations in the content of arachidonoyl chains in the adrenal gland phopsholipidome could account for disturbed adrenocortical hormone production. HighlightsO_LIThe adrenal gland lipidome is remodeled in obesity. C_LIO_LIArachidonoyl groups are abundant in the adrenal gland phospholipidome and increase in obesity. C_LIO_LIFADS2 is highly expressed in the adrenal gland and its expression is further increased in obesity. C_LIO_LIFADS2 inhibition blunts adrenocortical steroidogenesis in primary adrenal gland cell cultures, while arachidonic acid supplementation restores it. C_LI

cell biology↗

bioRxiv2020

HIF2α is a Direct Regulator of Neutrophil Motility

Orchestrated recruitment of neutrophils to inflamed tissue is essential during initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it is still unclear how these factors influence the migration of neutrophils to and at the site of inflammation either during their transmigration through the blood-endothelial cell barrier, or their motility in the interstitial space. Here, we reveal that activation of the Hypoxia Inducible Factor-2 (HIF2) due to deficiency of HIF-prolyl hydroxylase domain protein-2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. In vivo, the increased migratory capacity of PHD2-deficient neutrophils resulted in massive tissue accumulation in models of acute local inflammation. Using systematic RNAseq analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2-dependent neutrophil motility. Thus, we propose that the here identified novel PHD2-HIF2-RhoA axis is vital to the initial stages of inflammation as it promotes neutrophil movement through highly confined tissue landscapes.

immunology↗

bioRxiv2020

Machine learning pattern recognition and differential network analysis of gastric microbiome in the presence of proton pump inhibitor treatment or Helicobacter pylori infection

Although long thought to be a sterile and inhospitable environment, the stomach is inhabited by diverse microbial communities, co-existing in a dynamic balance. Long-term use of orally administered drugs such as Proton Pump Inhibitors (PPIs), or bacterial infection such as Helicobacter pylori, cause significant microbial alterations. Yet, studies revealing how the commensal bacteria re-organize, due to these perturbations of the gastric environment, are in the early phase. They mainly focus on the most prevalent taxa and rely on linear techniques for multivariate analysis. Here we disclose the importance of complementing linear dimensionality reduction techniques such as Principal Component Analysis and Multidimensional Scaling with nonlinear approaches derived from the physics of complex systems. Then, we show the importance to complete multivariate pattern analysis with differential network analysis, to reveal mechanisms of re-organizations which emerge from combinatorial microbial variations induced by a medical treatment (PPIs) or an infectious state (H. pylori).

systems biology↗

bioRxiv2018

Comprehensive and quantitative analysis of white and brown adipose tissue by shotgun lipidomics

Shotgun lipidomics enables an extensive analysis of lipids from tissues and fluids. Each specimen requires appropriate extraction and processing procedures to ensure good coverage and reproducible quantification of the lipidome. Adipose tissue (AT) has become a research focus with regard to its involvement in obesity-related pathologies. However, the quantification of the AT lipidome is particularly challenging due to the predominance of triacylglycerides, which elicit high ion suppression of the remaining lipid classes. We present a new and validated method for shotgun lipidomics of AT, which tailors the lipid extraction procedure to the target specimen and features high reproducibility with a linear dynamic range of at least 4 orders of magnitude for all lipid classes. Utilizing this method, we observed tissue-specific and diet-related differences in three AT types (brown, gonadal, inguinal subcutaneous) from lean and obese mice. Brown AT exhibited a distinct lipidomic profile with the greatest lipid class diversity and responded to high-fat diet by altering its lipid composition, which shifted towards that of white AT. Moreover, diet-induced obesity promoted an overall remodelling of the lipidome, where all three AT types featured a significant increase in longer and more unsaturated triacylglyceride and phospholipid species.\n\nThe here presented method facilitates reproducible systematic lipidomic profiling of AT and could be integrated with further -omics approaches used in (pre-)clinical research, in order to advance the understanding of the molecular metabolic dynamics involved in the pathogenesis of obesity-associated disorders.

physiology↗