2,190 research outputs found
TFG: a novel regulator of ULK1-dependent autophagy
No full textTRK-fused gene (TFG) is a protein implicated in multiple neurodegenerative diseases and oncogenesis. We have recently shown that, under starvation conditions, TFG contributes to spatial control of autophagy by facilitating Unc-51 like autophagy activating kinase 1 (ULK1)-microtubule-associated protein 1 light chain 3 gamma (MAP1LC3C) interaction to modulate omegasome and autophagosome formation. Defective TFG-mediated autophagy could thus be postulated as a possible contributor to ontogenesis or progression of TFG-related diseases
Targeting NDP52 in medulloblastoma to tackle cancer stem cells dissemination and therapy resistance
No full textAutophagy inhibition enhances Natural Killer cell- based therapy in high-risk Medulloblastoma
No full textMedulloblastoma (MB) is the most common pediatric brain tumor with Group3 (G3) subtype characterized by poor prognosis and therapy relapse. Autophagy is a self-degradative process increased in G3 MB stem cells (MBSCs) to contribute stemness and survival (Nazio et al., 2021). A promising therapeutic value in the treatment of high-risk MB is represented by Natural Killer cells (NKs)-based immunotherapy but it requires complementary approaches that break im- mune tolerance. To date, the role of autophagy-mediated mechanisms in regulating tumour heterogeneity and immune cells infiltration capability in the context of brain TME remains un- known as well as the role of autophagy in NK/CAR-NK mediated therapy is completely unex- plored. Herein, we are investigating the role of autophagy inhibition as a druggable mechanism to increase NK recognition and killing against MB G3. By flow cytometry analysis, we found low levels of NK-related activating ligands (ULBPs, CD155, CD112, MICA/B) in G3 cell lines and MBSCs derived by MB G3 patients compared to SHH subgroup. Intriguingly, genetic and pharmacologic inhibition of autophagy is able to increase NK-related ligand expression on cell surface of MB G3 cells. Additionally, by means of 2D and 3D models of MB G3 cells, we found that autophagy inhibition increases NK degranulation and MB G3 sensitiveness to NK-mediated cytotoxicity. Im- munotherapeutic strategies aimed at restoring and increasing the cytotoxic activity of NK cells in solid tumors, including the adoptive transfer of NK cells, are currently employed in preclinical and clinical studies. New strategies are necessary to make NK cells more resistant to the meta- bolically restrictive TME as well as to immunosuppressive molecules generated by the tumor. The completion of our project would be helpful to design a novel therapeutic approach for chil- dren with high-risk MB, aiming to a higher clinical response rate coupled with less toxicity as compared to conventional therapies
Should I stay or should I go? Spatio-temporal control of cellular anchorage by hematopoietic factors orchestrates tumor metastatic cascade
No full textAbstract The term “metastatic cascade” defines a process whereby few tumor cells complete a sequence of steps to leave the primary tumor to reach one or more sites elsewhere in the body, usually through the bloodstream to develop one or several metastases. Due to the nature and plasticity of cancer, unfortunately no specific and functional anti-metastatic drugs are available. In this Commentary, we are highlighting how four essential factors are able to induce adhesion-to-suspension transition (herein referred to as AST) in human cancer cells and how this process may play a key role in tumor metastasis. We further underlined the potential role of hematopoietic transcriptional regulators in reprogramming anchorage dependency of cells, supporting the possible targeting of AST factors as promising therapeutic strategy to overcome metastasis in solid tumor cells
The mitochondrial dynamics in cancer and immune-surveillance
No full textMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence
Exploring the role of mitophagy in medulloblastoma stem cells dissemination and therapy resistance
No full textMedulloblastoma (MB) is the most common malignant pediatric brain tumor comprising four main groups characterized by different genetic alterations and rate of mortality. Post-surgery radiotherapy (RT) is actually the standard of care for patients with MB; however, above 40% of patients remains incurable due to treatment failure. Limited treatment efficacy is mainly due to the presence of intrinsically resistant cancer stem cells (CSCs) that survive following comple- tion of standard therapies. Our laboratory recently identified autophagy activation in MB as a strong oncogenic process with translational significance for both patient stratification strategies and for the development of therapies targeting MB CSCs (Nazio et al 2021). Moreover, accumu- lating evidence indicates that autophagy supports metabolic rewiring of cancer cells and that regulators of mitophagy, selective degradation of mitochondria by autophagy, are frequently altered in CSCs. To date, the role of mitochondrial regulatory mechanisms and their effects on the current therapeutic regimen and tumour dissemination in MB remain unknown as well as mitochondrial properties unique to MBSCs need to be defined. Here, we have identified a novel pro-oncogenic role for the poorly studied mitophagy receptor NDP52 as a regulator of MB CSCs malignant phenotype; NDP52 upregulation supports MB CSCs aggressiveness by regulating: i) cell survival, ii) invasion capabilities, iii) mitophagy execution and iv) the response to RT. More- over, we are setting radiotherapy-adapted-(PDX) models of MB recurrence to study how radi- ation-induced changes in MBSCs could affect recurrence and metastasis post-radiotherapy by acting on mitochondria-related mechanisms. Therefore, understanding the molecular mecha- nisms and function of mitophagy in MB during different types of mitochondrial stress and dam- age may be critical for developing the next generation of MB treatment method
"The love that made hell, paradise." Ouida re-writing the Paolo and Francesca theme in Held in Bondage
No full textThe bestselling Victorian author Ouida reveals in her novels, and, in particular, Held in Bondage, an extraordinary knowledge od Dante, by using characters and themes from the Commedia. The Paolo and Francesca theme actually constitutes part of the plot of the novel and is to be found in many of her other works, short stories and non-fiction writing
HERStory Makers 2023: Francesca Fotheringham
No full textFrancesca Fotheringham is a postdoctoral research associate at the University of Edinburgh studying educational psychology with a focus on neurodiversity. She took part in HERStory Makers 2023.What is HERStory Makers?HERStory Makers is a social media competition for female-identifying early career researchers to share their research, their career journeys, and to inspire the next generation. Winners are selected by public vote. HERStory Makers is also part of EXPLORATHON, Scotland's contribution to European Researchers' Night.In 2022-23, EXPLORATHON Francescasupported by the Engineering & Physical Sciences Research Council [grant number EP/X020762/1].Author contributions to contentFrancesca conceived, planned, and recorded the video content. Kirsty Ross edited the video content to insert HERStory Maker credits, added subtitles, and reduce video length to below Twitter/X limit of 2 mins and 20 secs.</p
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