Oncology
Oncology.jpg

Due to its major role in many cellular pathways, the UPS has been extensively reported to be deregulated in several pathologies.  We aim at elucidating the molecular events that trigger improper functioning of the UPS in the context of oncogenesis, and how these events may be targeted in the development of a novel therapeutic strategy.  Importantly, we found a direct functional role for CRLs in the context of tumorigenesis and metastatic progression.  We found that CRL1-FBXO11 targets the BCL6 oncoprotein for degradation.  BCL6 overexpression is the primary driver of oncogenesis in diffuse large B cell lymphoma (DLBCL), and FBXO11 is mutated in 20 percent of DLBCLs, resulting in BCL6 overexpression in these tumors.  Separately, we found a tissue-specific role for CRL1-FBXW7 in cell survival, by targeting p100/NF-κB2, an inhibitor of NF-κB signaling, for degradation.  In multiple myeloma cells, which are addicted to constitutive NF-κB signaling, the disruption of FBXW7-dependent p100 degradation by the inhibition of GSK3β results in cell death.  We also found that the tumor suppressor PTEN competes with FBXL2 for IP3R3 binding, and the CRL1-FBXL2-dependent degradation of IP3R3 is accelerated in Pten-/- mouse embryonic fibroblasts and PTEN-null cancer cells.  We then showed that inhibiting IP3R3 degradation with a small molecule in PTEN-deregulated cancers represents a valid therapeutic strategy.  We characterized the function of CRL1-EMI1 in the pathogenesis of breast cancer, highlighting a novel mechanism of resistance to the class of FDA-approved PARP1 inhibitors. We discovered CRL4-AMBRA1 as the ubiquitin ligase of D-type cyclins in diffuse large B-cell lymphoma, supporting the development of inhibitors that simultaneously target CDK2/4/6. We also focused on the role of CRL3-Keap1 in inducing metastasis in lung cancers, as well as on the role of CRL1-FBXL7 in mediating cell migration, extravasation, and invasion of other tissues during metastatic progression in pancreatic and prostate adenocarcinomas.