Titolo della tesi: IKKβ-mediated constitutive inflammation and metabolic reprogramming in the extravasation of brain-seeking triple-negative breast cancer cells
Metastasis is a critical stage in cancer progression, where tumor cells spread from their original site to distant organs, often leading to dire consequences. Our research delves into the intricacies of the extravasation process, wherein tumor cells exit the bloodstream to infiltrate the parenchyma of target organs. In this thesis we try to understand the proclivity of breast cancer, the most common malignancy in women worldwide, to form metastases within the brain. This research investigates the role of the NF-κB signaling pathway in driving breast cancer brain metastasis, focusing on its involvement in promoting inflammation and metabolic reprogramming, key processes for cancer cell survival and spread. Using the MDA-MB-231, 4T1, and E0771 cell models, which represent triple-negative breast cancer cell lines, as well as brain-seeking breast cancer cell lines derived from these parental lines, we explored how these cells exploit glutamate metabolism and inflammatory cytokines to invade the brain. Our findings reveal that brain-metastatic cells overexpress IKKβ kinase, resulting in NF-κB constitutive activation, reducing the levels of inhibitors like IKBα and Tax1bp1, and producing specific cytokines, including IL-8 and GRO alfa, beta and gamma. These cytokines weaken the blood-brain barrier (BBB), facilitating the entry of cancer cells into the brain. We also demonstrated that IKKβ regulates the expression of glutamate transporters. Glutamate is a highly abundant amino acid in the brain. Moreover, the overexpression of glutamate transporters EAAT1 and EAAT2 in metastatic cells enhances glutamate uptake, supporting the metabolic needs of brain metastatic cells increasing their migratory potential. Inhibition of IKKβ and blockade of glutamate transporters were shown to significantly reduce cancer cell migration and disrupt brain metastasis formation. This study fills critical gaps in understanding how the brain microenvironment supports metastasis and highlights IKKβ inhibitors and glutamate transporter blockers as promising therapeutic strategies. These findings offer potential new avenues for improving treatment outcomes for breast cancer patients at high risk of developing brain metastases.