Malignant melanoma is the deadliest type of skin cancer. Its incidence is still increasing and when not diagnosed at early stages its prognosis is poor. Such aggressiveness is due to its metastatic invasive features, high genetic mutation rate and resistance to chemotherapeutic treatments. The attempt to find possible genetic oncotargets and pharmacological treatments aiming to reduce the aggressivity of this cancer and ameliorate its prognosis is very challenging. In this work, by exploiting a human metastatic melanoma xenograft zebrafish model, both aspects were explored, studying on one side the effects of genetic engineering on transcription factor activity in melanoma and on the other side how pharmacological treatments based on a fungal molecule can be exploited to restrain the invasive potential of this tumor. Indeed, several transcription factors affect cellular processes by modulating gene expression in cancers. In particular, it has been reported a higher expression of RUNX2 in melanoma cells than in normal melanocytes. To investigate the role of this transcription factor in melanoma development, a deletion in the Runt domain of RUNX2 was obtained with Crispr/Cas9 in a human metastatic melanoma cell line. The present study pointed out that cells harbouring the deletion in the Runt domain when transplanted in zebrafish had reduced abilities to proliferate, to migrate and to form metastases. Furthermore, the deletion affected neoangiogenesis indicating the potential role of RUNX2 and particularly of its Runt domain as a new melanoma oncotarget. On the other side, a hint came from studies that underlined the anti-neoplastic potential of vegetal and fungal lectins due to their specific binding to the T antigen of human cancer cells. In fact, it has been shown that a fungal lectin purified from the fruiting bodies of Boletus edulis mushrooms named BEL β trefoil was able to decrease viability and proliferative ability of human metastatic melanoma cells in vitro. The present work showed the ability of BEL β trefoil to spread in the tissue of treated zebrafish xenografts and to reduce melanoma cell migration and formation of metastases, indicating this lectin as an effective biomolecule with potential of counteracting melanoma disease progression.

IDENTIFICATION OF NEW TARGETS AND THERAPEUTIC STRATEGIES FOR THE TREATMENT OF MELANOMA

Marchetto, Giulia
2021

Abstract

Malignant melanoma is the deadliest type of skin cancer. Its incidence is still increasing and when not diagnosed at early stages its prognosis is poor. Such aggressiveness is due to its metastatic invasive features, high genetic mutation rate and resistance to chemotherapeutic treatments. The attempt to find possible genetic oncotargets and pharmacological treatments aiming to reduce the aggressivity of this cancer and ameliorate its prognosis is very challenging. In this work, by exploiting a human metastatic melanoma xenograft zebrafish model, both aspects were explored, studying on one side the effects of genetic engineering on transcription factor activity in melanoma and on the other side how pharmacological treatments based on a fungal molecule can be exploited to restrain the invasive potential of this tumor. Indeed, several transcription factors affect cellular processes by modulating gene expression in cancers. In particular, it has been reported a higher expression of RUNX2 in melanoma cells than in normal melanocytes. To investigate the role of this transcription factor in melanoma development, a deletion in the Runt domain of RUNX2 was obtained with Crispr/Cas9 in a human metastatic melanoma cell line. The present study pointed out that cells harbouring the deletion in the Runt domain when transplanted in zebrafish had reduced abilities to proliferate, to migrate and to form metastases. Furthermore, the deletion affected neoangiogenesis indicating the potential role of RUNX2 and particularly of its Runt domain as a new melanoma oncotarget. On the other side, a hint came from studies that underlined the anti-neoplastic potential of vegetal and fungal lectins due to their specific binding to the T antigen of human cancer cells. In fact, it has been shown that a fungal lectin purified from the fruiting bodies of Boletus edulis mushrooms named BEL β trefoil was able to decrease viability and proliferative ability of human metastatic melanoma cells in vitro. The present work showed the ability of BEL β trefoil to spread in the tissue of treated zebrafish xenografts and to reduce melanoma cell migration and formation of metastases, indicating this lectin as an effective biomolecule with potential of counteracting melanoma disease progression.
Zebrafish, Melanoma, Xenotransplant, Runx2, Lectin
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1045734
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