The lamin-associated telomeric factor Ft1 as co-driver in cancer aggressiveness

The nuclear envelope (NE) integrity is essential for cellular function, and disruptions can lead to genomic instability, a hallmark of cancer. The lamin-associated telomeric factor Ft1 (AKTIP in human) plays a role in NE stability through interactions with lamins and ESCRT machinery. Engineered mouse models deficient in both Ft1 and p53, have shown that the Ft1 loss enhanced the invasiveness and aggressiveness of p53-dependent lymphomas, suggesting that Ft1 depletion may act as a co-driver of tumor progression. This thesis aims to elucidate the direct role of Ft1 in NE integrity and to establish methodologies to investigate how Ft1 contributes to the aggressive lymphoma phenotype observed in vivo. Our in vitro findings demonstrate that Ft1 depletion in interphase mammalian cells leads to an increase in NE abnormalities, including blebbing and ruptures, which result in heightened nuclear fragility. These results indicate that Ft1 is essential for NE integrity maintenance during interphase. To further assess whether the observed tumor phenotype in vivo arises from cell-autonomous mechanisms or requires additional factors beyond T-cell involvement, we implemented two experimental approaches. The first approach involved generating a constitutive Ft1 knockout model, as well as a T-cell-specific Ft1 knockout model, both in a p53-null background. The second approach utilized a newly developed Ft1-depleted lymphoma cell line, which was transplanted into wild-type mice to determine if Ft1 depletion enhances tumor progression through cell-autonomous effects. These novel methodologies provide a foundation for future research into the role of Ft1 in p53-dependent lymphomagenesis in murine models and may represent valuable tools for broader cancer research applications.