Research lines
DECODING THE MOLECULAR CROSSTALK BETWEEN CANCER CELL METABOLISM AND TUMOR MICROENVIROMENT
We aim at understanding if metabolic rearrangements of cancer cells affect the composition of the extracellular matrix (ECM) and if this translates into an enhancement of neoplastic growth. We focus on in vitro and in vivo models of Malignant Peripheral Nerve Sheath Tumor (MPNST), an aggressive and invasive cancer that develops either sporadically or in Neurofibromatosis Type 1 patients and is associated with a high ECM production. We perform whole mount immunofluorescence staining and biochemical assays on 3D cell culture systems that mimic the MPNST architecture and represent ideal platforms to test potential drugs, whose effectiveness can be further validated in our in vivo MPNST model.
sMPNST spheroid immunofluorescence
Macrophage staining in genetically engineered mice developing MPNSTs
ELUCIDATING THE ROLES OF TUMOR-ASSOCIATED MACROPHAGES
Our aim is to understand whether tumor associated macrophages (TAMs) undergo metabolic changes that exert pro-neoplastic functions in MPNSTs. We co-culture TAMs and MPNST cells to understand how their metabolic crosstalk influences pro-tumor biological routines (e.g. migration, invasion). We also employ genetically engineered mouse models developing MPNST to characterize in vivo MPNST-associated macrophages and their roles in neoplastic progression. The ultimate goal is to identify targetable players in MPNST-associated macrophages for drawing novel therapeutic strategies.
3D culture of melanoma cells
UNRAVELING NEW METABOLIC LIABILITIES IN MELANOMA
Melanoma is the deadliest form of skin cancer with an inherent metabolic plasticity due to the upregulation to MAPK pathways. Such metabolic adaptations are central in supporting the acquisition of both the malignant phenotype and the drug resistance. The identification of dysregulated metabolic pathways could open new perspectives in the development of effective pharmacological strategies. By applying a stepwise approach spanning from metabolomics analysis to in vitro and in vivo tumorigenic assays we aim at identifying metabolic liabilities of melanoma cells that will support the development of new pharmacological strategies.
THE CROSSTALK BETWEEN METABOLIC REWIRING AND EPIGENETIC REMODELLING IN DLBCL
Diffuse large B-cell lymxphoma (DLBCL) is the most common Non-Hodgkin Lymphoma. The high proliferation rate of B cells in the germinal center requires continuous chromatin remodeling that also depends on the accumulation of metabolites. This research line has the purpose to study how accumulation of the oncometabolite succinate elicited by the mitochondrial chaperone TRAP1 is crucial in driving lymphoma genesis and progression. By applying biochemical assays and genome expression profile analyses, both in cells and in patient-derived tumors, we aim at unveiling which genes are regulated by TRAP1 and how these may influence DLBCL growth.
TRAP1 staining on adult primary DLBCL patient sample
DESIGN OF INNOVATIVE AND TAILORED THERAPEUTIC APPROACHES TO TACKLE TUMORS
Neurofibromatosis type 1 (NF1) derived tumors are benign or highly malignant neoplasms originating from Schwann cells. They represent a relevant clinical challenge as they are often inoperable and resistant to treatments. We have developed a peptide-based anti-neoplastic approach targeting hexokinase 2 (HK2), a key component of the metabolic machinery of tumor cells. Anti-HK2 peptides displace HK2 from mitochondria and specifically induce tumor cell death both in vitro and in vivo. This strategy is based on modular and adaptable cell penetrating peptide (HK2pep), which is activated by extracellular proteases cleavage. The ultimate goal of this project is to exploit NF1-derived tumors extracellular proteases expression to improve the release and the therapeutic effects of HK2pep.
IDENTIFICATION OF INHIBITORS SELECTIVELY TARGETING THE PRO-NEOPLASTIC MITOCHONDRIAL CHAPERONE TRAP1
The mitochondrial chaperone TRAP1, a conserved member of the Hsp90 family, has been identified as a master regulator of the mitochondrial bioenergetics in several tumor cell types. Targeting TRAP1 with selective allosteric inhibitors has emerged as an effective strategy in reducing the tumorigenicity of many tumor cell models. To improve the effect of these drug-like molecules, we are developing second generation inhibitors whose efficacy will be tested both in in vitro and in vivo tumor models. This research lines aim at identifying new selective TRAP1 inhibitors that, alone or in combination with other chemotherapeutics, could constitute a valuable anti-tumor strategy.