Biology subjects

Bilgin, M.

Publications and source records attributed to Bilgin, M..

4 recordsLinked to original sources

bioRxiv2026

Prostaglandin E2 facilitates reciprocal crosstalk between intestinal smooth muscle tissue and epithelium in tumor development

Colorectal cancer arises from intestinal epithelial cells and is driven by the accumulation of aberrant signaling events that disrupt intestinal stem cell (ISC) homeostasis. While stromal regulation of the ISC niche is increasingly recognized, the contribution of the underlying/adjacent smooth muscle tissue (SMT) remains poorly characterized. In particular, the potential crosstalk between normal or tumoral epithelium and the SMT is largely unexplored. Here, we investigate the ability of the SMT in modulating normal and tumorigenic epithelial biology, and the impact of the tumoral epithelium on the underlying SMT. Mechanistically, by using imaging analyses, transcriptomics, and mass spectrometry, we identify the SMT-derived factor Prostaglandin E2 (PGE2) as the key driver of epithelial dedifferentiation, promoting YAP transcriptional activation, organoid enlargement, and spheroid morphology in intestinal epithelial organoids following SMT supernatant exposure. Conversely, we show that non-invasive tumoral epithelium induces significant changes in the underlying SMT. Tumor-associated SMT shows structural remodeling, inflammation, and reduced muscle fitness. Furthermore, we detected increased prostaglandin signaling, including upregulation of PGE2 synthase Ptgs1 (COX1), in the SMT underneath the epithelial tumor. Our results reveal a communication between the tumoral epithelium and the underlying SMT prior to metastasis, which could be a facilitating step for tumoral extramural progression. Taken together, these findings highlight a novel tumor-stroma interaction.

Molecular Biology↗

bioRxiv2025

Lipid Landscape of human cells

Eukaryotic cells synthesise thousands of lipid species, yet the principles that organise them across compartments remain unclear. Here we introduce PAP-SL, parallel (immuno)affinity purification coupled to shotgun lipidomics, to map [~]300 lipid species across six compartments of human cells and uncover general rules of lipid organisation. Correlation analyses of stoichiometric lipid compositions resolved archetypal distribution trajectories. Biosynthetic origin set the baseline: mitochondrial and lysosomal pathways generated confined pools, whereas the ER acted as a dispatch hub shaping downstream membrane territories. The ER established the saturated plasma membrane through transfer of phosphatidylserine, sphingolipids, and cholesterol, together with species-level selection of more saturated glycerophospholipids across diverse headgroups, while less-saturated species moved unselectively into mitochondria. The ER also channelled ether-linked glycerophospholipids to lysosomes, forming a territory dominated by ether phosphatidylcholine that collapsed under ethanolamine-driven metabolic rewiring. PAP-SL defines a framework to resolve lipid organisation and its metabolic plasticity in health and disease.

systems biology↗

bioRxiv2024

Lipidomic Profiling Reveals Shared and Distinct Pathological Signatures in Sporadic Parkinson's Disease and GBA Mutation Carriers: Implications for Disease Mechanisms

Parkinsons Disease (PD) is a neurodegenerative disorder characterised by the deposition of protein-lipid inclusions, containing alpha-synuclein, neuronal cell loss and disruptions in lipid metabolism such as those associated with GBA mutations. GBA mutations are together an important genetic risk factor for PD and are associated with a decrease in glucocerebrosidase, a lysosomal glycoprotein encoded by GBA, increase in alpha-synuclein and changes in sphingolipids levels and composition. However, the extent of lipid metabolism disruptions associated to PD and their contributions to disease progression remain unclear. In this study, we used a combination of biochemical and lipidomic analyses of amygdala from healthy controls (HC) and people with sporadic (sPD) or GBA-associated PD (PD-GBA) to investigate the correlation between alpha-synuclein, glucocerebrosidase and lipids. We found extensive metabolic remodelling of brain lipids, including increased free cholesterol, diacylglycerides, sphingolipids and specific glycerophospholipids in amygdala from people with sPD and disease duration above 30 years (sPD>30y) and from people with PD carriers of a GBA risk mutation (PD-GBArisk) relative to HC. The levels of free cholesterol, diacylglycerides, sphingolipids and specific glycerophospholipids all correlated positively with pathological S and negatively with GCase activity. In contrast, the levels of phosphatidylethanolamine and cardiolipin only correlated positively with GCase activity. Moreover, we observed changes in the distribution of species for sphingolipids and glycerophospholipids in opposite directions for two categories of PD cases. We found a shift from short to long sphingomyelin and ceramide and from long to short phosphatidylserine and phosphatidylethanolamine in sPD>30y and PD-GBArisk cases and the opposite in sPD<10y and PD-GBAsevere cases. The relative proportion of lipid species affected in these samples all correlated with glucocerebrosidase activity and pathological alpha-synuclein levels. Together, these findings highlight the correlation between glucocerebrosidase, pathological alpha-synuclein and lipid levels in PD. Moreover, the identified opposite changes in lipid distribution for two categories of people with sPD and PD-GBA underscore the importance of patient stratification in clinical trials aiming at reverting PD-related lipid changes.

neuroscience↗

bioRxiv2023

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/543387v1_figu1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1645e05org.highwire.dtl.DTLVardef@58ad70org.highwire.dtl.DTLVardef@1e2c57aorg.highwire.dtl.DTLVardef@112fcbd_HPS_FORMAT_FIGEXP M_FIG C_FIG Squalene synthase (SQS) is an essential enzyme in the mevalonate pathway whose abundance and activity control cholesterol biosynthesis and homeostasis. Although catalytic inhibitors of SQS have been developed to attenuate cholesterol, none so far have been approved for therapeutic use. Herein we sought to develop SQS degraders using targeted protein degradation (TPD) as an approach to lower overall cellular cholesterol content. We found that KY02111, a small molecule ligand of SQS, could selectively cause SQS to degrade in a proteasome-dependent manner. In contrast, compounds based on the same scaffold linked to E3 ligase recruiting ligands led to SQS stabilization. Whole cell proteomic analysis found KY02111 to reduce only the levels of SQS, while lipidomic analysis determined that KY02111 treatment concomitantly reduced cellular cholesteryl ester content. SQS stabilizers were shown to shield SQS from its natural turnover without recruiting their matching E3 ligase. Our work shows that degradation of SQS is possible despite a challenging biological setting and lays the groundwork for future development of either SQS degrading or stabilizing probes.

cell biology↗