Biology subjects

Sebastian, D.

Publications and source records attributed to Sebastian, D..

4 recordsLinked to original sources

bioRxiv2026

Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling

Tumor heterogeneity is a major determinant of tumor progression and therapeutic resistance, yet the contribution of metabolism to intratumoral heterogeneity still remains poorly explored. Here, we find that pyruvate dehydrogenase kinase-1 (Pdk1) expression defines metabolically distinct cancer cell populations in colorectal tumors. Image-based spatial single-cell phenotyping shows that Pdk1-high cells are associated with tumor progression in orthotopic models of colorectal cancer (CRC). Genetic ablation experiments demonstrate the role of Pdk1-high cells in tumor growth, 5-fluorouracil chemoresistance and tumor relapse. Mechanistically, we identify a link between Pdk1-driven metabolic states and specific cell phenotypes, where Pdk1-high cancer cells exhibit an EMT, stem cell-like phenotype characterized by increased interferon (IFN) signaling. Mitochondrial remodeling in Pdk1-high cells leads to the release of mitochondrial DNA to the cytosol and activation of IFN pathways, promoting Pdk1-driven phenotypes. Inhibition of IFN signaling impairs the tumorigenic and aggressive features of Pdk1-high cancer cells, thus establishing a functional connection between metabolic heterogeneity, cell-intrinsic IFN signaling and aggressive CRC.

cancer biology↗

bioRxiv2025

Fasting-induced hepatic gluconeogenesis is compromised in Anxa6-/- mice

Maintaining constant blood glucose levels is essential for energizing glucose-dependent tissues. During the fed state, insulin lowers elevated blood glucose, while in the fasted state, glucagon maintains blood glucose levels through hepatic stimulation of fatty acid oxidation, glycogenolysis, and gluconeogenesis (GNG). The liver plays a crucial role in these metabolic adaptations. Deregulation of GNG is a hallmark of type 2 diabetes mellitus (T2DM), driven by hepatic insulin resistance, elevated glucagon levels, and excess circulating free fatty acids. Despite normal insulin-sensitive control of glucose levels and effective glycogen mobilization, Anxa6 knockout (Anxa6-/-) mice display rapid hypoglycaemia during fasting. This metabolic disarrangement, in particular during the early stages of fasting is characterized by a low respiratory exchange ratio (RER) and increased lipid oxidation during the diurnal period, indicating a reliance on lipid oxidation due to hypoglycaemia. Elevated glucagon levels during fasting suggest deficiencies in GNG. Further analysis reveals that Anxa6-/- mice are unable to utilize alanine for hepatic GNG, highlighting a specific impairment in the glucose-alanine cycle in fasted Anxa6-/- mice, underscoring the critical role of ANXA6 in maintaining glucose homeostasis under metabolic stress. During fasting, slightly reduced expression levels of alanine aminotransferase 2 (Gpt2) and lactate dehydrogenase (Ldha2), enzymes converting alanine to pyruvate, and the hepatic alanine transporter SNAT4 might contribute to these observations in the Anxa6-/- mice. These findings identify that ANXA6 deficiency causes an inability to maintain glycolytic metabolism under fasting conditions due to impaired alanine-dependent GNG.

physiology↗

bioRxiv2018

Impairment of neuronal mitophagy by mutant huntingtin

Neuronal homeostasis depends on the proper functioning of different quality control systems. The accurate degradation of dysfunctional mitochondria by mitophagy is essential for maintaining mitochondrial quality and quantity in neurons. Huntingting protein (Htt) can interact with numerous other proteins and thereby perform multiple biological functions in the cell. We investigated the role of Htt during neuronal mitophagy in post-mitotic differentiated striatal neurons avoiding artificial overexpression of mitophagy-related proteins. Our study shows that Htt promotes the physical proximity of different protein complexes during initiation of the mitophagy process. Htt is needed to promote the ULK1 complex activation, the recruitment of the essential receptors of mitophagy -optineurin and NDP52- and the interaction of these receptors with LC3-II. Mutant Htt also causes a gain of toxic function avoiding the formation of the Beclin1-Vps34 initiation complex. We report that the presence of the expanded polyQ tract can affect the efficiency of neuronal mitophagy and consequently promote the accumulation of damaged mitochondria and increase oxidative stress, leading to mitochondrial dysfunction and contributing to neurodegeneration in Huntingtons disease.

neuroscience↗

bioRxiv2017

A Comprehensive Reanalysis Of Publicly Available GWAS Datasets Reveals An X Chromosome Rare Regulatory Variant Associated With High Risk For Type 2 Diabetes.

The reanalysis of publicly available GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics and pathophysiology of complex diseases. We demonstrate this by gathering and reanalyzing public type 2 diabetes (T2D) GWAS data for 70,127 subjects, using an innovative imputation and association strategy based on multiple reference panels (1000G and UK10K). This approach led us replicate and fine map 50 known T2D loci, and identify seven novel associated regions: five driven by common variants in or near LYPLAL1, NEUROG3, CAMKK2, ABO and GIP genes; one by a low frequency variant near EHMT2; and one driven by a rare variant in chromosome Xq23, associated with a 2.7-fold increased risk for T2D in males, and located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a known modulator of insulin sensitivity. We further show that the risk T allele reduces binding of a nuclear protein, resulting in increased enhancer activity in muscle cells. Beyond providing novel insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel analytical approaches.

genetics↗