Phd in EXPERIMENTAL MEDICINE

Thesis title: "Nuovi approcci terapeutici nel melanoma e adenocarcinoma polmonare attraverso la generazione di organoidi da pazienti sottoposti a intervento chirurgico"

Cancer represents a complex ecosystem composed not only of neoplastic cells but also of numerous non-tumor cells, including stromal and immune components that collectively define the tumor microenvironment (TME). Interactions among cancer cells, the extracellular matrix, and non neoplastic cells critically modulate disease progression, metastatic dissemination, and therapeutic response. Among the most profoundly altered cellular processes, metabolic reprogramming particularly lipid metabolism has emerged as a key determinant of tumor survival and adaptability. Stearoyl-CoA Desaturase 1 (SCD1), an enzyme involved in the synthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs), plays an essential role in maintaining metabolic plasticity and regulating cancer stem cells (CSCs). Its overexpression has been associated with proliferation, invasiveness, and drug resistance in several cancers, including melanoma and non-small cell lung adenocarcinoma (NSCLC). Both pharmacological and genetic inhibition of SCD1 have been shown to reduce CSCs viability, induce apoptosis, and restore sensitivity to conventional treatments. In parallel, lipid metabolism profoundly influences immune and stromal cells within the TME, contributing to the establishment of an immunosuppressive milieu that promotes tumor progression and therapeutic resistance. The integrated study of metabolic and immunological interactions within the TME therefore represents a promising avenue for identifying new predictive biomarkers and developing innovative therapeutic strategies. Within this framework, the present research project aims to investigate the interactions among lipid metabolism, the tumor microenvironment, and CSCs in melanoma and lung adenocarcinoma, with the goal of identifying new molecular targets and personalized therapeutic approaches. To this end, three-dimensional (3D) in vitro models including patient-derived organoids (PDOs) have been developed and characterized. These models faithfully recapitulate the genetic, molecular, and functional heterogeneity of the original tumor. Such models constitute powerful preclinical tools for studying drug response and validating personalized therapeutic strategies, paving the way toward a deeper understanding of resistance mechanisms and a concrete advancement of precision medicine in oncology.