Biology subjects

Finocchiaro, G.

Publications and source records attributed to Finocchiaro, G..

4 recordsLinked to original sources

bioRxiv2026

A chemically reactive and Raman-active non-canonical amino acid reveals photocycle complexity in a blue-light receptor

Photosensory protein function spans multiple time and length scales, demanding integrative approaches. We introduce 4-diacetylenyl-phenylalanine (DAF), a dual-purpose non-canonical amino acid (ncAA) that enables both chemical control and spectroscopic readout of photoreceptor dynamics. Genetically encoded in E. coli, DAF combines a reactive diyne for bioorthogonal ligations (thiols, azides, tetrazines) with a strong, solvatochromic Raman signal in the cell-silent region. Applied to the light-oxygen-voltage (LOV) transcription factor EL222, DAF enables multifaceted interrogation of its photocycle. We engineer a covalently cross-linked variant that suppresses light-driven conformational changes and DNA binding, and generate a donor-acceptor construct for Forster resonance energy transfer (FRET) tracking of photoinduced structural dynamics. Time-resolved stimulated Raman spectroscopy following flavin mononucleotide (FMN) excitation reveals additional processes -from vibrational energy transfer to local unfolding-spanning femtoseconds to milliseconds. DAF thus constitutes a versatile tool to resolve protein dynamics with high spatiotemporal resolution.

biochemistry↗

bioRxiv2025

Tumor-initiating genetics and therapy drive divergent molecular evolution in IDH-mutant gliomas

Astrocytomas and oligodendrogliomas are slow-growing and treatment-sensitive IDH-mutant gliomas diagnosed at ages 30-50. Local tumor regrowth and treatment resistance is inevitable resulting in 3-10 year astrocytoma and up to >20 years oligodendroglioma survival. We sought to identify genetic changes associated with tumor evolution in response to therapy through multi-timepoint whole-genome/whole-exome sequencing of 206 IDH-mutant glioma patient samples collected through the Glioma Longitudinal Analysis (GLASS) Consortium. We validated known genomic markers of tumor progression, including hypermutation and CDKN2A homozygous deletion, and discovered novel genetic alterations that distinguish the response to treatment in astrocytomas compared to oligodendrogliomas. Point mutations in PIK3CA, PIK3R1, and NOTCH1 were newly acquired in recurrent oligodendrogliomas and associated with increased mutation rates. Focal oncogene amplifications, together with CDKN2A homozygous deletions, were associated with an increase in recurrence-specific chromosomal imbalances in astrocytomas. Mutational signature analysis revealed additional differences and detected enrichment for the SBS11, and SBS119 mutational signatures after temozolomide treatment in both IDH-glioma subtypes, whereas astrocytomas showed increased ID8 signatures after radiotherapy. These signatures suggest that the genomes of oligodendroglioma and astrocytoma adapt to the selective pressures of tumor progression and treatment in different ways. However, in both IDH-mutant glioma subtypes we observed a convergence of acquired driver gene alterations with genome-wide changes and worse patient outcomes, signaling selection of treatment-refractory clones. By identifying new prognostic markers and delineating the genomic divergence of oligodendrogliomas and astrocytomas after diagnosis, our results suggest that different DNA damage response mechanisms are engaged following chemo- and radiation therapy.

cancer biology↗

bioRxiv2023

RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression

Despite well-documented metabolic and hematopoietic alterations during tumor development1, the mechanisms underlying this crucial immunometabolic intersection have remained elusive. Of particular interest is the ligand-activated transcription factor retinoic acid-related orphan receptor 1 (RORC1/ROR{gamma}), whose activity is boosted by cholesterol metabolites2, acting as a modulator of cancer-related emergency myelopoiesis3, while hypercholesterolemia itself is associated with dysregulated myelopoiesis4,5. Here we show that both cancer growth and hypercholesterolemic diet can independently or cooperatively activate ROR{gamma}-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2 polarization of tumor-associated macrophages (TAMs), thereby supporting cancer spread. Moreover, we report that tumor development enhances the hepatic production of IL-1{beta} and IL-6, which in turn promote upregulation of hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, as we confirmed in models of fibrosarcoma, melanoma, colorectal (CRC), and lung cancer, as well as in CRC, non-small-cell lung cancer (NSCLC), breast (BRC), pancreatic ductal adenocarcinoma (PDAC), biliary tract carcinoma (BTC) and pancreatic neuroendocrine tumor (PNET) patients. Importantly, lowering cholesterol levels prevents MDSC expansion and M2 TAM accumulation in a ROR{gamma}-dependent manner, unleashing specific anti-tumor immunity and improving the efficacy of anti-PD-1 immunotherapy. Overall, we identify ROR{gamma} as a novel sensor of lipid disorders in cancer bearers, bridging hypercholesterolemia and pro-tumor myelopoiesis.

immunology↗

bioRxiv2018

Altered function of the glutamate aspartate transporter GLAST in glioblastoma

In glioma patients, high levels of glutamate can cause brain edema and seizures. GLAST, a glutamate-aspartate transporter expressed by astrocytes with a role in glutamate uptake, is highly expressed on the plasma membrane of glioblastoma (GBM) cells, and its expression significantly correlates with shortened patient survival. Here, it was demonstrated that inhibition of GLAST expression limited the progression and invasion of GBM xenografts. Magnetic resonance spectroscopy was used to measure glutamate in GLAST-expressing gliomas showing that these tumors exhibit increased glutamate concentration. Despite their GLAST expression, GBM stem-like cells (GSCs) released rather than took up glutamate due to their lack of Na+/K+-ATPase. Overexpression of Na+/K+-ATPase in these cells restored glutamate uptake and induced apoptosis. The therapeutic relevance of targeting GLAST in gliomas was assessed using the inhibitor UCPH-101. In glioma-bearing mice, a single intratumoral injection of UCPH-101 significantly increased survival by decreasing GLAST expression and inducing apoptosis. Thus, GLAST has a novel role in GBM that appears to have crucial relevance in glutamate trafficking and may thus be a new therapeutic target.

cancer biology↗