Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis.

Advances in bladder cancer (BCa) treatment have been hampered by the lack of predictive biomarkers and targeted therapies. Here, we demonstrate that loss of the tumor suppressor NUMB promotes aggressive bladder tumorigenesis and worsens disease outcomes. Retrospective cohort studies show that NUMB-loss correlates with poor prognosis in post-cystectomy muscle-invasive BCa patients and increased risk of muscle invasion progression in non-muscle invasive BCa patients.

CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer.

Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis.

A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing.

The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM.

HMGA1 protein expression in familial breast carcinoma patients.

HMGA protein overexpression is associated with a highly malignant phenotype and it is also causally related to neoplastic cell transformation. Our previous results have shown that HMGA1 was not expressed in normal breast tissue whereas HMGA1 staining was intense in 25% of hyperplastic lesions with cellular atypia and in 60% of sporadic ductal carcinomas. Moreover, HMGA1 protein levels were significantly correlated with c-Erb-B2 expression.

Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumor.

Protein ubiquitination is critical for many cellular processes, through its ability to regulate protein degradation and various signaling mechanisms. In the ubiquitin (Ub) system, substrate specificity is achieved through the E3 family of Ub ligases. Because alterations of the ubiquitination machinery have been reported in human cancers, the selective interference with Ub ligases might represent a powerful therapeutic tool.