Phd in GENETICS AND MOLECULAR BIOLOGY

Thesis title: Decoding Cancer Plasticity: Long Non-Coding RNAs and Microenvironmental Signals Driving Phenotypic Transitions in Melanoma and Prostate Cancer

Cellular plasticity is a fundamental mechanism driving cancer progression, therapeutic resistance, and lineage reprogramming. Beyond the accumulation of genetic alterations, tumour cells can undergo dynamic phenotypic transitions that enable adaptation to environmental pressures and anticancer therapies. This thesis investigates these processes in two tumour types, melanoma and prostate cancer. The first part of the study focuses on phenotype switching in melanoma. Transcriptomic analyses identified two distinct cellular states, a proliferative and an invasive state, and revealed the long non-coding RNAs (lncRNAs) LINC00504 and LINC00520 as key components of the regulatory network controlling this transition. Both lncRNAs were identified as direct MITF targets and were associated with poor patient survival. Functional studies demonstrated that they act as miRNA sponges to sustain the proliferative program, whereas their silencing promotes a switch toward a more invasive phenotype. The second part of the thesis investigates lineage plasticity in prostate cancer using the ProMPt (Prostate cancer Modelling Platform) organoid biobank. We identified Epidermal Growth Factor (EGF) as a major driver of culture-induced resistance that masks androgen receptor (AR) dependency under standard conditions. To overcome this limitation, we developed an organoids-fibroblasts co-culture system that restores sensitivity to androgen deprivation while maintaining long-term organoid growth. Using this platform in combination with CRISPR-mediated genome editing, we demonstrated that distinct genetic backgrounds direct different adaptive trajectories under therapeutic and microenvironmental stress. In particular, APC loss promoted neuroendocrine differentiation, whereas RB1 inactivation favoured the emergence of a double-negative phenotype.