Bladder cancer organoids as a functional system to model different disease stages and therapy response.

Bladder Cancer (BLCa) inter-patient heterogeneity is the primary cause of treatment failure, suggesting that patients could benefit from a more personalized treatment approach. Patient-derived organoids (PDOs) have been successfully used as a functional model for predicting drug response in different cancers. In our study, we establish PDO cultures from different BLCa stages and grades. PDOs preserve the histological and molecular heterogeneity of the parental tumors, including their multiclonal genetic landscapes, and consistently share key genetic alterations, mirroring tumor evolution in longitudinal sampling. Our drug screening pipeline is implemented using PDOs, testing standard-of-care and FDA-approved compounds for other tumors. Integrative analysis of drug response profiles with matched PDO genomic analysis is used to determine enrichment thresholds for candidate markers of therapy response and resistance. Finally, by assessing the clinical history of longitudinally sampled cases, we can determine whether the disease clonal evolution matched with drug response.

Antineoplastic activity of lentiviral vectors expressing interferon-alpha in a preclinical model of primary effusion lymphoma.

The peculiar site of development of primary effusion lymphoma (PEL) highlights a specific role of body cavities in the pathogenesis of this neoplasia. We used a xenograft murine model of PEL to characterize the contribution of the host microenvironment to PEL growth. The activity of a murine (ie, host-specific) interferon-alpha(1) (IFN-alpha(1))-expressing lentiviral vector (mIFN-alpha(1)-LV) was compared with that of a human (h) IFN-alpha(2)b-LV. LVs efficiently delivered the transgene to PEL cells and conferred long-term transgene expression in vitro and in vivo. Treatment of PEL-injected severe combined immunodeficiency mice with hIFN-alpha(2)b-LV significantly prolonged mice survival and reduced ascites development. Interestingly, mIFN-alpha(1)-LV showed an antineoplastic activity comparable with that observed with hIFN-alpha(2)b-LV. As mIFN-alpha(1) retained species-restricted activity in vitro, it probably acted in vivo on the intracavitary murine milieu. mIFN-alpha(1)-treated murine mesothelial cells were found to express tumor necrosis factor-related apoptosis-inducing ligand and to significantly trigger apoptosis of cocultured PEL cells in a tumor necrosis factor-related apoptosis-inducing ligand-dependent manner. These data suggest that the interaction between lymphomatous and mesothelial cells lining the body cavities may play a key role in PEL growth control and also indicate that the specific targeting of microenvironment may impair PEL development.