Detailed projects description
Glioblastoma (GBM) is a highly lethal primitive brain tumor whose therapeutic possibilities are strongly limited by their ineffectiveness against GBM tumor-initiating cells (GBM TICs). Being resistant to radiation and chemotherapy, GBM TICs drive recurrence after therapy, and because of this are designed as clinically relevant targets.
Our laboratory is interested in elucidating the role of lysine specific histone demethylase 1 (LSD1) in the modulation of patient-derived GBM TIC biological properties and epigenetic landscape, and to unravel the mechanisms through which its chemical inhibition can modulate GBM TIC stem cell-like phenotype and tumorigenic potential.
Our final goal is to evaluate in vitroand in vivothe therapeutic potential of LSD1 chemical inhibition, alone and/or in combination with other drugs, to provide novel and effective treatment modalities against this devastating disease.
Breast cancer is a heterogeneous disease that remains the second leading cause of death among women worldwide. Despite advances in the prevention, detection and adjuvant therapy of breast cancer (BC), a substantial proportion of patients are diagnosed with metastatic disease. Brain metastasis (BM) is one of the major types of breast cancer metastasis: approximately 10-15% of patients with metastatic breast cancer develop brain metastasis during the course of their disease. Brain relapse typically occurs several years after the removal of the primary breast tumor, suggesting that disseminated cancer cells must acquire mutations and specialized functions to take over this organ.
It has become well accepted that metastatic cells display features reminiscent of the tumor-initiating cells (TICs). Based on the functional definition of the TICs, cells capable of forming a brain metastases could be considered as brain metastasis-initiating cells (MICs).
A collection of metastasis-initiating cells (MICs) isolated from breast-derived brain metastases is available in the laboratory and has been deeply characterizedin vitroand in vivo.
Understanding the molecular mechanisms that drive MIC maintenance will be critical to design novel therapeutic approaches to manage brain metastases.
Preclinical cellular models
Our laboratory is interested in designing novel preclinical cellular models thorough the establishment of organoid culture systems from three representative tumor models, brain metastases, glioblastomas and those rare tumors for which no cellular models are available (e.g. thymoma). Notably, in organoid cultures cells are forced to grow in vitroin all directions, thus mirroring their in vivogrowth. This approach should preserve the histological architecture, genomic and expression landscape of the original tumor, even after a long-term expansion in culture.
Glioblastoma extracellular vesicles
GBM releases in blood a great amount of extracellular vesicles (EVs) containing tumor-specific molecules (proteins, DNA, RNA). Our laboratory has identified a specific proteomic signature of GBM EVs and has demonstrated that plasma EV concentration represents per sea solid indicator of GBM presence. Our aim is to exploit the informative power of plasma EVs to gain full access to GBM molecular shape, allowing the early diagnose and to follow treatment response. Our studies take advantage from all the last-generation technologies to study EVs, namely multi-omics approaches, electron microscopy, in vitro and in vivo models, physical characterization and specific isolation and sorting. Ultimately, our work will offer a unique and novel method to diagnose GBM, to select the best disease management and to follow treatment response overcoming the limitations of the current standard therapy based on imaging and surgery. Plasma EV analysis will eventually allow for tailored therapeutic approaches based on longitudinal monitoring of specific molecular signatures of the tumor. This would be of tremendous value for the patient by allowing the application of precision medicine without the risk of a surgical procedure to obtain tumor tissue.