Cristiana Alberghina

Ciclo: XXXVI

Data inizio: 31/10/2020

Curriculum: Biotecnologie biomediche e precliniche

Borsa: UniCT

Titolo tesi: Intercellular communication and tumor microenvironment rewiring in glioblastoma pathophysiological response to radiotherapy

Abstract: Tumor microenvironment (TME), composed by a milieu of stromal and immune cells, is one of the critical players in glioblastoma (GBM) progression and heterogeneity. GBM progression is supported by a wide range of mechanisms, which involve several intracellular processes that influence metabolic arrangement, genetic and epigenetic state and the tumor milieu. GBM represents a challenging clinical condition due to the plethora of dynamic processes occurring in TME, stimulating immunosuppression mechanisms and triggers therapy resistance. Current approach employed to counteract GBM progression takes into account the synergistic effect mediated by surgical resection, chemotherapy and involved field radiotherapy (RT). RT represents the gold-standard treatment for this WHO grade IV glioma. Unfortunately, RT is characterized by severe off-target effects, affecting central nervous system (CNS)-resident cells. Tumor associated microglia/macrophages (TAMs) are largely represented in TME of CNS tumors, showing a critical role in GBM progression, favouring immune-escape processes and stemness features. Herein, we first evaluated GBM proliferation and migration in response to specific stimuli, promoting intercellular communication. Then, we moved to evaluate the off-target effects induced by RT, focussing on the related consequences on the microglia-GBM axis. On one hand, CXs established critical interactions with Sonic Hedgehog signalling pathway, which were responsible for GBM infiltrative phenotype, promoting tumor aggressiveness and modulating the heterocellular crosstalk within the TME. On the other hand, GBM cells and its milieu undergo significant alterations due to the impact of radio treatment. We focussed on the interplay between 2-15 Gy irradiated (IR) microglia-derived conditioned media (CM) and naïve GBM cells. We observed that tumor cells survival was preserved, avoiding death mechanisms and favouring GBM clone formation. IR microglia-derived CM exposure showed also a key role not only in maintaining mitochondrial mass and fitness but also preventing mitochondrial ROS production. The administration of metformin, together with IR microglia CM exposure, induced a decrease in tumor cell proliferation. The evidence provided suggests that RT-derived off-target effects alter microglia state, promoting GBM aggressiveness and growth through the release of factors which are able to sustain metabolic rewiring toward oxidative phosphorylation. Our observations highlight the essential role of the interplay between tumor and healthy surrounding cells, which is the main cause of metabolic reshaping and epigenetic modifications, leading to the alteration of TME response and resulting in an immunosuppressive phenotype. This work aims to encourage further investigations on TME remodelling, focussing on immune response alteration and GBM-TME crosstalk reshaping.

Tutor: Parenti

Data Conseguimento Titolo: 20/12/2023

Linkedin: https://www.linkedin.com/in/cristiana-alberghina-phd-52423626b/

Email: cristiana952311@gmail.com - cristianaalberghina@cnr.it 

Periodi all'estero- Sede e data: University of Ljubljana (Slovenia) - Medical Faculty – Laboratory of Neuroendocrinology - Molecular Cell Physiology at the Institute of Pathophysiology - 12/12/2022 al 12/06/2023 

Esperienze post-Dottorato ed attuale occupazione: Dal 01/03/2024 – in corso: Post-doc research fellow at Institute of Bioimaging and Complex Biological Systems, National Research Council (IBSBC-CNR) – Cefalù (PA), Italy