Molecular genetics

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide. Due to the lack of effective early diagnostic strategies, LC is frequently diagnosed at advanced stages, resulting in poor prognosis, with 5-year survival rates ranging from 9% to 18%. Although low-dose computed tomography (LDCT) is currently the recommended screening tool and has been shown to reduce lung cancer mortality, the development of complementary, minimally invasive biomarkers remains a critical unmet clinical need. MicroRNAs (miRs) are small non-coding RNAs that play key roles in the regulation of multiple biological processes. Their expression is frequently dysregulated in cancer, including NSCLC, making them attractive candidates as diagnostic and prognostic biomarkers. Notably, circulating miRs present in biofluids exhibit high stability, being resistant to nuclease degradation and to extreme temperature and pH conditions, thus fulfilling key requirements for clinical applicability. Accordingly, circulating miRs have emerged as promising tools for the early detection of lung cancer. MicroRNAs (miRNAs) have emerged as promising candidates for cancer biomarkers due to their central role in the regulation of multiple biological processes and their frequent deregulation in tumorigenesis. In lung cancer, alterations in circulating miRNA profiles have been associated with disease onset, progression, and response to therapy. Notably, miRNAs released into biofluids display high stability and resistance to degradation, making them particularly suitable for minimally invasive diagnostic applications. Current research in our laboratory focuses on the identification and characterization of selected circulating miRNA candidates with potential relevance for the early detection of non-small-cell lung cancer (NSCLC). These miRNAs may originate from different cellular compartments, including tumor cells, stromal cells, and immune cells, and can be released into the circulation through both passive and active mechanisms, such as vesicle-mediated secretion. Through their ability to modulate pathways involved in cell differentiation, proliferation, invasion, immune regulation, and microenvironment remodeling, circulating miRNAs are likely to reflect key biological features of the tumor and its interaction with the host. We aim to evaluate the clinical utility of circulating miRNAs as biomarkers for early-stage NSCLC using a comprehensive and multidisciplinary approach. This includes the validation of selected miRNA signatures in prospective cohorts, the assessment and optimization of innovative technologies for miRNA detection in serum, and the investigation of the cellular sources contributing to circulating miRNA pools. In addition, combinatorial miRNA-based strategies will be explored to improve diagnostic accuracy and to support the stratification of NSCLC subtypes.

Lung cancer represents one of the leading causes of cancer-related mortality worldwide. Therefore, it is of fundamental importance to characterize the genes involved in tumor initiation and progression, as well as to identify prognostic biomarkers and novel therapeutic targets that may act as synthetic lethal partners in combination with currently available targeted therapies, in order to prevent or delay the onset of therapeutic resistance. For several years, our laboratory has been investigating the role of PRODH in this context. In particular, we have characterized its transcriptional regulation by the p53 family of transcription factors, identifying the corresponding consensus sequences within the gene. Moreover, we have demonstrated that PRODH expression in lung adenocarcinoma cell lines leads to a reduction in cell survival and proliferative capacity, as a result of reactive oxygen species (ROS)-mediated induction of cellular senescence. However, cellular senescence is also associated with the activation of a pro-inflammatory secretory phenotype, characterized by the production of cytokines capable of remodeling the tumor microenvironment, thereby promoting the recruitment of innate immune cells and endothelial cells. In addition, this condition may contribute to the acquisition of resistance to specific therapeutic strategies. These aspects are currently being investigated through functional studies conducted in vitro and in vivo.