Biology subjects

De Bardi, M.

Publications and source records attributed to De Bardi, M..

3 recordsLinked to original sources

bioRxiv2023

NRF2 connects Src tyrosine kinase to ferroptosis resistance in glioblastoma

Glioblastoma (GBM) is a severe brain tumor characterized by an extremely poor survival rate of patients. GBM cancer cells escape to standard therapeutic protocols consisting of combination of ionizing radiation (IR) and alkylating drugs that trigger DNA damage, by rewiring of signaling pathways. In recent years, the upregulation of factors that counteract ferroptosis has been highlighted as a major driver of cancer resistance to IR, although the molecular connection between the activation of oncogenic signaling and the modulation of ferroptosis has not been clarified yet. Here we provide the first evidence for a molecular connection between the constitutive activation of tyrosine kinases and resistance to ferroptosis. Src tyrosine kinase, a central hub on which Receptor Tyrosine Kinases deregulated signaling converge in cancer, leads to the stabilization and activation of NRF2 pathway, thus promoting resistance to IR-induced ferroptosis. These data suggest that the upregulation of Src-NRF2 axis may represent a vulnerability for combined strategies that, by targeting ferroptosis resistance, enhance radiation sensitivity in glioblastoma.

cancer biology↗

bioRxiv2021

Partial resistance to HDAC inhibitors in FAPs of dystrophic muscles at late stages of disease is associated to epigenetic and transcriptional features of cellular senescence.

Pharmacological treatment of Duchenne Muscular Dystrophy (DMD) with histone deacetylase inhibitors (HDACi) is currently being tested in clinical trials. Pre-clinical studies performed in mdx mice - the mouse model of DMD - have shown that HDACi promote compensatory muscle regeneration, while inhibiting fibro-adipogenic degeneration, by targeting fibro-adipogenic progenitors (FAPs); however, these beneficial effects are restricted to early stages of disease progression. We show here that FAPs from late stage mdx mice exhibit epigenetic and transcriptional features of senescence that could not be fully reversed by HDACi. In particular, genome-wide increase in H3K9/14 acetylation at gene promoters of Senescence Associated Secretory Phenotype (SASP) genes was associated with their upregulation in late stage mdx FAPs. Treatment with the HDACi Trichostatin A (TSA) could inhibit SASP gene activation in FAPs, by decreasing H3K9/14 acetylation. Conversely, combinatorial decrease of H3K27 and/or H3K9/14 acetylation at promoters of genes required for cycle activation and progression was associated with their downregulation in FAPs from late stage mdx mice. However, these epigenetic and transcriptional alterations could not be reversed by TSA, due to a general resistance exhibited by FAPs from late stage mdx mice to HDACi-induced H3K9/14 hyperacetylation. Overall, this data reveal that disease-associated features of senescence develop in FAPs of DMD muscle through epigenetically distinct and pharmacologically dissociable events, and suggests that HDACi might at least retain anti- fibrotic and inflammatory activity at late stages of DMD, by repressing FAP-derived SASP.

pharmacology and toxicology↗

bioRxiv2020

Pharmacological tuning of microRNA in FAP-derived Extracellular Vesicles by HDAC inhibitors promotes regeneration and reduces fibrosis in dystrophic muscles.

Functional interactions between cellular components of the muscle stem cell (MuSC) niche regulate the regenerative ability of skeletal muscles in physiological and pathological conditions; however, the identity of the mediators of these interactions remains largely unknown. We show here that fibro-adipogenic progenitor (FAP)-derived Extracellular Vesicles (EVs) mediate microRNA transfer to MuSCs, and that exposure of dystrophic FAPs to HDAC inhibitors (HDACi) increases the intra-EV levels of a subset of microRNAs (miRs), which cooperatively target biological processes of therapeutic interest, including regeneration, fibrosis and inflammation. In particular, we found that increased levels of miR206 in EVs released from FAPs of muscles from Duchenne dystrophic patients or mice (mdx) exposed to HDACi were associated with enhanced regeneration and inhibition of fibrosis of dystrophic muscles. Consistently, EVs from HDACi-treated dystrophic FAPs could stimulated MuSC activation and expansion ex vivo, and promoted regeneration, while inhibiting fibrosis and inflammation of dystrophic muscles, upon intramuscular transplantation, in vivo. These data reveal a potential for pharmacological modulation of FAP-derived EVs content as novel strategy for focal therapeutic interventions in Duchenne Muscular Dystrophy (DMD) and possibly other muscular diseases. Brief SummaryExtracellular Vesicles from HDACi-treated dystrophic FAPs promote regeneration, while inhibiting fibrosis and inflammation of dystrophic muscles

cell biology↗