Comprendere il ruolo di p130Cas nel cancro al pancreas nella chemioresistenza e nella metastatizzazione.

Pancreatic cancer ranks as the third-leading cause of cancer-related deaths, with a projected trajectory to become the second by 2030. Its grim prognosis is attributed to late-stage diagnoses, surgical complexities, and a dearth of effective treatments. Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form, often originates from potentially curable non-invasive lesions when detected early. Risk factors, whether modifiable or not, contribute to pancreatic cancer. Unmodified factors usually mean to be age, family history or gene mutations. KRAS gene mutations are present in 80-90% of PDAC followed by mutations in tumour suppressor genes like CDKN2A, TP53, and SMAD4. KRAS activation triggers various downstream signalling pathways, notably the PI3K/Akt pathway, pivotal in fostering metastasis and presenting potential therapeutic targets. This study focuses on p130Cas, an adaptor protein within the Cas family, and its significant role in several cancers, including pancreatic cancer, impacting metastasis, chemoresistance, and invasion. p130Cas has been associated with promoting chemoresistance in various cancers, including colon and lung cancer, suggesting its inhibition could enhance treatment outcomes. It also plays a role in epithelial-mesenchymal transition (EMT) and serves as a key regulator of cancer cell growth and invasiveness in lung and colon cancers. However, there is not so much evidence about the role of p130Cas in pancreatic cancer development and progression. During this work we tried to get more insights on this protein in the case of chemoresistance and metastatization of pancreatic cancer. The primary objective of this study was to elucidate the role of p130Cas in pancreatic cancer, contributing to a deeper understanding of the disease. Murine cell lines, that were derived from mice harbouring KRAS and p53 mutations, were used, and p130Cas expression was manipulated using lentiviral vectors, either downregulated or overexpressed, with its regulation confirmed through Western blot analysis. To evaluate role of p130Cas in developing of resistance to chemotherapy, cell viability assays were performed in both 2D and 3D cultures. Metastatic ability of cancer cells lacking or overexpression p130Cas was investigated via trans-well migration-invasion assays, employing specific inhibitors to probe the connection between p130Cas and the PI3K/AKT pathway in the invasion process. Results demonstrated that p130Cas is intricately involved in the PI3K/AKT pathway, regulating the phosphorylation of AKT. Downregulation of p130Cas sensitized pancreatic cancer cells to chemotherapeutic drugs in both 2D and 3D cultures, whereas overexpression of p130Cas promoted resistance to paclitaxel in 3D cultures. Furthermore, cells with elevated p130Cas exhibited enhanced invasiveness compared to those with unaltered expression. Notably, inhibiting the PI3K/Akt pathway using an Akt inhibitor reversed the invasive capacity of cells overexpressing p130Cas. These findings underscore p130Cas as a promising target for future research in pancreatic cancer, whether as a therapeutic target or a diagnostic marker. Evaluating p130Cas expression in patients holds the potential to predict the risk of metastatization and optimize subsequent treatment strategies. Targeting p130Cas can be useful in case of avoiding metastatization or enhancing the sensitivity of cancer cells to chemotherapy treatment. These hypotheses need further research for validation.