Identification and characterization of new genes modulated by the p53 tumor suppressor protein with a potential impact on the prediction of pro-metastatic processes

Mutations in the TP53 tumor suppressor gene play a critical role in neoplastic transformation. These mutations affect the expression of many genes involved in cell cycle regulation, apoptosis, DNA repair, autophagy, and senescence. TP53 mutations are frequently observed in cancers such as triple-negative breast cancer (TNBC), a particularly invasive form of metastatic carcinoma. Comprehensive profiling of p53 mutations and their targets could significantly improve metastasis and therapy resistance prediction, underpinning the development of personalized cancer treatments. In this study, preliminary RNA sequencing identified differentially expressed genes in MDA-MB-231 TNBC cells expressing the p.R280K p53 protein and their derivative p53 knock-out cell line, T1. P.R280K elimination notably affected the migration and adhesion capacity of MDA-MB-231 cells. This work aimed to identify genes differentially expressed involved in these processes and validate their gene expression. Several genes involved in cell migration and proliferation were identified and validated, with p53-dependent regulation studied to assess their contribution to an aggressive, pro-metastatic phenotype in tumors harboring mutant p53 proteins. Among these, ENPP1 emerged as the most interesting gene, up-regulated by mutant p53 and absent in p53 knock-out cells, with pro-migratory and anti-immune functions. Our findings suggest a consistent interplay between p.R280K p53 and ENPP1 in promoting tumor cells’ proliferation and invasion while suppressing the cGAS/STING immune pathway, thereby hindering the antitumor immune response. These results establish the groundwork for further investigation into the p.R280K p53-ENPP1 interaction, emphasizing the need for early detection and strategies to prevent aggressive, metastatic, and therapy-resistant tumor progression.