Biology subjects

Bianchi, K.

Publications and source records attributed to Bianchi, K..

7 recordsLinked to original sources

bioRxiv2026

β3-Integrin controls pericyte metabolic states and shapes tumour-stromal metabolic crosstalk in breast cancer

Pericytes are emerging as dynamic regulators of the tumour microenvironment. Yet, their role in tumour metabolism remains elusive. Here, we investigate whether {beta}3-integrin regulates pericyte metabolic state and shapes stromal-tumour metabolic interactions in breast cancer. By integrating spatial and single-cell transcriptomics from human breast tumours with multi-omics profiling of tumour-derived pericytes in vitro, we identify two {beta}3-integrin-dependent metabolic states. {beta}3-integrin-high pericytes display a metabolically active phenotype characterised by increased glycolysis and enhanced de novo serine/glycine synthesis, supporting collagen production. In contrast, {beta}3-integrin loss induces a lipid-associated state, marked by neutral lipid accumulation and lipid droplets. Mechanistically, {beta}3-integrin regulates this metabolic switch via mTOR signalling. Importantly, these states extend beyond pericytes, with adjacent cancer cells shifting towards fatty acid oxidation and lipid use near {beta}3-integrin-low pericytes. Together, our findings establish {beta}3-integrin as a key metabolic switch in pericytes and highlight their role in driving tumour metabolic plasticity.

cancer biology↗

bioRxiv2025

Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development

To grow and divide cells must tightly coordinate anabolic programs with the availability of nutrients and growth factors. This balance is especially critical during postnatal development, when biosynthetic and energetic demands are high, and nutrient supply and neonates have to adapt to periods of fasting. These conditions place acute stress on the proteostasis network, making autophagy essential for nutrient recycling. We found that the chaperone aryl hydrocarbon receptor-interacting protein (AIP) supports both arms of this metabolic balance: promoting anabolic PI3K-AKT signaling for mTORC1 activation and enabling catabolic processes such as proteasomal degradation and autophagy. Loss of AIP causes a severe neonatal metabolic disorder, where affected infants fail to thrive postnatally. Our findings establish AIP as a central regulator of neonatal metabolic adaptation and cellular homeostasis. One Sentence SummaryAIP integrates nutrient sensing and protein recycling to sustain neonatal survival.

developmental biology↗

bioRxiv2025

Coenzyme A homeostasis regulates hypoxic signalling via UBFD1in triple-negative breast cancer

Hypoxia-inducible factors (HIFs) orchestrate cellular responses to oxygen deprivation and are frequently activated in triple-negative breast cancer (TNBC), driving metastasis and poor prognosis1,2. However, the full mechanisms of how HIFs are activated are not completely understood. It has been long noted that certain tumours have decreased levels of coenzyme A compared to surrounding tissues3,4, but the functional consequences of this remain unknown. Here, we identify Coenzyme A Synthase (CoAsy) as a novel regulator of HIF signalling. We demonstrate that CoAsy loss stabilises HIF-1 and HIF-2 independently of the canonical oxygen sensing pathway. Proximity-labelling proteomics revealed that CoAsy deficiency disrupts the association between HIF-1 and the proteasome through UBFD1, a novel CoA-binding protein that scaffolds HIF for degradation. UBFD1s CoA-dependent interaction with HIF- is mediated by its PH domain, which undergoes CoAlation, an understudied post-translational modification. COASY loss of heterozygosity occurs in [~]1/3 of breast cancer patients and correlates with increased HIF activity, lack of hormone receptor expression and poor patient outcome. In vivo studies confirm that restoring CoAsy expression in tumours suppresses metastasis to the lung. These findings uncover a critical metabolic checkpoint regulating hypoxic signalling and identify CoAsy as a potential biomarker and therapeutic target in aggressive breast cancers.

molecular biology↗

bioRxiv2024

Biallelic Loss of Molecular Chaperone Molecule AIP Results in a Novel Severe Multisystem Disease Defined by Defective Proteostasis

Children born with deleterious biallelic variants of the chaperone aryl hydrocarbon receptor interacting protein (AIP) have a novel pediatric metabolic disease presenting a severe, complex clinical phenotype characterized by failure to develop following birth. Analysis of Aip knockout mouse embryonic fibroblasts and patient-derived dermal fibroblasts revealed that AIP was required to support proteostasis; including proteasome activity, induction of autophagy and lysosome function. aip knockout zebrafish, recapitulated the phenotype of the children; dying at an early stage of development when autophagy is required to adapt to periods of starvation. Our results demonstrate that AIP plays a crucial role in initiating autophagy and maintaining proteostasis in vitro and in vivo. One Sentence SummaryHomozygous loss of the chaperone AIP results in a novel pediatric disease exhibiting multiple features of a lysosomal storage disease.

molecular biology↗

bioRxiv2024

Metabolic remodelling in hiPSC-derived myofibres carrying the m.3243A>G mutation

Mutations in mitochondrial DNA cause severe multisystem disease, frequently associated with muscle weakness. The m.3243A>G mutation is the major cause of Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke Like episodes (MELAS). Experimental models that recapitulate the disease phenotype in vitro for disease modelling or drug screening are very limited. We have therefore generated hiPSC-derived muscle fibres with variable heteroplasmic mtDNA mutation load without significantly affecting muscle differentiation potential. The cells are excitable and show physiological characteristics of muscle fibres and show well organised myofibrillar structure. In cells carrying the m.3243A>G, the mitochondrial membrane potential and oxygen consumption were reduced in relation to the mutant load. We have shown through proteomic, phosphoproteomic, and metabolomic analyses that the m.3243A>G mutation variably affects the cell phenotype in relation to the mutant load. This variation is reflected by an increase in the NADH/NAD+ ratio, which in turns influences key nutrient-sensing pathways in the myofibres. This model enables detailed study of the impact of the mutation on cellular bioenergetics and on muscle physiology with the potential to provide a platform for drug screening.

cell biology↗

bioRxiv2024

Pyruvate metabolism dictates fibroblast sensitivity to GLS1 inhibition during fibrogenesis

Fibrosis is a chronic disease characterized by excessive extracellular matrix (ECM) production which leads to destruction of normal tissue architecture and disruption of organ function. Fibroblasts are key effector cells of this process and respond to a host of pro-fibrotic stimuli, including notably the pleiotropic cytokine, TGF-{beta}1, which promotes fibroblast to myofibroblast differentiation. This is accompanied by the simultaneous rewiring of metabolic networks to meet the biosynthetic and bioenergetic needs of contractile and ECM-synthesizing cells, but the exact mechanisms involved remain poorly understood. In this study, we report that extracellular nutrient availability profoundly influences the TGF-{beta}1 transcriptome of primary human lung fibroblasts (pHLFs) and the "biosynthesis of amino acids" emerges as a top enriched transcriptional module influenced by TGF-{beta}1. We subsequently uncover a key role for pyruvate in influencing the pharmacological impact of glutaminase (GLS1) inhibition during TGF-{beta}1-induced fibrogenesis. In pyruvate replete conditions which mimic the physiological concentration of pyruvate in human blood, GLS1 inhibition is ineffective in blocking TGF-{beta}1-induced fibrogenesis, as pyruvate is able to be used as the substrate for glutamate and alanine production via glutamate dehydrogenase (GDH) and glutamic-pyruvic transaminase 2 (GPT2), respectively. We further show that dual targeting of either GPT2 or GDH in combination with GLS1-inhibition is required to fully block TGF-{beta}1-induced collagen synthesis. These findings embolden a therapeutic strategy aimed at additional targeting of mitochondrial pyruvate metabolism in the presence of a glutaminolysis inhibitor in order to interfere with the pathological deposition of collagen in the setting of pulmonary fibrosis and potentially other fibrotic conditions.

cell biology↗

bioRxiv2019

The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism

The I{kappa}B kinase {varepsilon} (IKK{varepsilon}) is a key molecule at the crossroads of inflammation and cancer. Known for its role as an activator of NF{kappa}B and IRF3 signalling leading to cytokine secretion, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKK{varepsilon} remodels cellular metabolism is currently unknown. Here we used a combination of metabolomics and phosphoproteomics to show that IKK{varepsilon} orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and serine biosynthesis. Acting independently of its canonical signalling role, IKK{varepsilon} upregulates the serine biosynthesis pathway (SBP) mainly by limiting glucose and pyruvate derived anaplerosis of the TCA cycle. In turn, this elicits activation of the transcription factor ATF4 and upregulation of the SBP genes. Importantly, pharmacological inhibition of the IKK{varepsilon}-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a set of basal ER negative and highly proliferative human breast cancer tumours, IKK{varepsilon} and PSAT1 expression levels are positively correlated corroborating the link between IKK{varepsilon} and the SBP in the clinical context.

cancer biology↗