Andrea Di Cristofori

2010 Degree in Medicine and Surgery (110/110 cum laude) at Università degli Studi di Milano – Milano, Italy
2017 Board certified neurosurgeon (12/07/2017 – 70/70 cum laude) at Università degli Studi di Milano – Milano, Italy
2014 – 2015 Senior clinical fellow (Neuro-oncology and vascular neurosurgery) at Salford Royal Foundation Trust, Greater Manchester (UK)
2018 – Part I European Neurosugical Societies certification
From 2018 Neurosurgeon at Fondazione IRCCS San Gerardo dei Tintori di Monza, Italy
From 2011 till December 2023: 1053 surgeries as first surgeon mainly for cranial neurosurgery (336 craniotomies) and 481 surgeries as assistant neurosurgeon
Clinical activities: I am mainly dedicated to cranial neurosurgery with special interest to neuro-oncology and hydrocephalus.
Research activities: starting from 2011 I have dedicated myself to research both clinical and basic/traslational with main interest on neuro-oncology (including gliomas, meningiomas and pituitary adenomas).
I have participated to several peer – reviewed pubblications (including book chapters), congresses as speaker and courses as tutor.

PhD research project

V-ATPase in glioblastoma: analysis of exosomes produced by patients’ derived stem cell culture and during the neuro-oncological follow-up

Gliomas are primary brain tumors originating from glial cells. They are classified according to the 2016 WHO classification into three grades from II to IV. Grade III and IV gliomas are considered aggressive primary brain tumors with a poor prognosis which depends on several factors. In particular, the most aggressive and malignant of the primary brain tumors are the so called Glioblastoma Multiforme (GBM), that are classified as WHO grade IV gliomas. Patients with GBM have a poor overall survival although surgical resection and adjuvant chemo-radiation therapy. Tumor recurrence is generally expected. The use of alkylating agents has improved the prognosis of HGGs but after the introduction of Temozolomide (TMZ) in 2005 as standard first line treatment, no other improvement has been made. Moreover, there is not a standardized second line treatment after tumor recurrence.

GBMs have been found to have a small population of cancer stem cells (CSC) that contribute to tumor spreading, invasion, proliferation and maintenance.

H + Vacuolar ATPase (V-ATPase) is a ubiquitinously expressed multisubunits proton pump that is mainly involved in the acidification of endosomes and lysosomes in eukaryotic cells. This protein is made of a membrane-embedded V0 sector, which regulates protons permeability, and an enzymatic V1 ATPase sector.

This protein is also crucial for maintaining a normal intracellular pH in both normal conditions and during anaerobic glycolytic reactions, like those sustaining the neoplastic cellular metabolism. In this setting, the excess of protons is counterbalanced by the extrusion of H + from the intracellular to the extracellular environment through the activation and overexpression of V-ATPase. For this reason, many tumors show a V-ATPase overexpression, whose inhibition is related to a dysregulation of cytosolic pH that ultimately leads to the activation of pro-apoptotic proteins, alteration of metabolic chain reactions and of endosomal vesicles. Other than providing those functions, V-ATPase plays a crucial role in chemoresistance of solid tumors.

In 2015 it was demonstrated that V-ATPase is overexpressed in HGGs while it is poorly expressed in LGGs. From a clinical point of view, it was demonstrated how expression of V-ATPase is related to the patient’s prognosis independently from other clinical risk factors.

Exosomes (EXos) are nano-sized microvescicles (40-150 nm) actively produced from the late endosomal machinery. These particles are associated with multiple biological functions both in normal and pathological conditions and are devoted to a network that allow intercellular communication. Because of these features, EXos are involved in tumor spreading and in tumor drug resistance. Moreover, in case of IDH wt gliomas, V1G1 has demonstrated to be loaded in microvescicles of CSCs neurospheres harvested from patients with GBM. This fact highlights the possible role of V1G1 subunit as blood marker for GBM but there is a lack of evidence that it can be found in patients too.

In this view, the project aims to understand and better investigate the possible roles that V-ATPase may play as marker of treatment response during the neuro-oncological follow-up studying the EXos loads.