The aim of our research is to map CSC biomarkers from patient-derived tumor samples and to study proteins involved in GBM generation and progression.
i) We recently demonstrated that RAI is a novel regulator of GBM invasion. RAI expression in cancer stem cells obtained from human GBM tumors allows their infiltration throughout brain parenchyma, preventing complete surgical resection and allowing relapse (Ortensi B. et al., 2012). Uncovering the molecular mechanisms regulating cancer infiltration would permit to set up new therapeutic strategies to block GBM invasion. We are now performing microRNA arrays to identify potential microRNAs involved in RAI regulation in CSCs, aiming at the identification of clinically relevant targets.
ii) We recently demonstrated that CLIC1 (Chloride intracellular channel-1) is variably expressed in patient-derived GBM neurospheres and is enriched in the stem/progenitor compartment of the neurosphere (manuscript under review). Moreover, its silencing in GBM stem/progenitor cells negatively influences both proliferative capacity and self-renewal properties in vitro and impairs the in vivo tumorigenic potential. In addition to its role inside the tissue, CLIC1 has been identified as a secreted protein and detected in exosomes released from different cell types including glioma cells. Our goal is to elucidate the biological and clinical impact of CLIC1 secreted protein in glioblastoma.
iii) A project currently ongoing in the lab aims at determining the CSC frequency in freshly dissociated human GBM samples, by means of in vitro and in vivo assays. This would fill an important gap in the knowledge of the brain tumor biology.
iv) CSCs have been identified in different types of human cancer as the responsible of tumor initiation and propagation. In human GBM these cells have been isolated mostly on the basis of the expression of the cell surface protein CD133. We have recently demonstrated that the functional role of CD133 in the stem cell compartment is strictly related to its cell surface localization, giving a new insight in the biological function of this protein in GBM stem cells (Brescia et al., 2013). We are interested in the study of potential CSC markers that could be used in clinical applications.
v) Brain metastases are the most common malignancy of the CNS. The knowledge of the biology regulating brain metastasis is fragmentary. The existence of metastasis-initiating cells has not yet been proved, although some evidences suggest that these cells might be found within subpopulations of CSCs. Our projects aim to i) identify specific molecular alterations in the brain metastases; ii) understand the mechanisms of organ-specific metastatic program: study of the relevance of the blood-brain barrier and/or the specific niche in brain metastases formation; iii) define the molecular subtypes that identify patients at high risk of developing brain metastases. To achieve these aims we will study brain metastases derived from breast tumors.