Lipid Metabolism and Cell Cycle Regulation in Cancer
Metabolism and prostate cancer
Genetic alterations in cancer define specific metabolic pathways that support their survival and growth. Thus, simultaneous targeting of selected metabolic enzymes and “driving” oncogenes may be cancer cell-selective. We discovered that USP2a stabilizes fatty acid synthase (FASN) by preventing its degradation and showed that FASN is a metabolic oncogene. This was the first report of a metabolic oncogene in prostate cancer. Significant interactions between body mass index, FASN polymorphisms and FASN expression suggest FASN as a potential link between obesity and poor PCa outcome. We found that the energy sensor AMPK, a master regulator of metabolism, represents an ideal target in prostate cancer. Fatty acid synthesis is required at the G2/M, represents a novel “lipogenic checkpoint” and may be therapeutically exploited with FASN inhibitors or AMPK activators. We have developed a method to perform metabolic profiling in formalin-fixed, paraffin embedded tissue.
Role of de-ubiquitinating enzymes in prostate cancer
My first RO1 aimed at the identification of de-ubiquitinating enzymes expressed in prostate cancer and their targets. As mentioned in “contribution to science 1” we discovered that USP2a binds to and stabilizes fatty acid synthase (FASN) by preventing its degradation (ref 1a). We demonstrated that USP2a behaves as an oncogene in prostate cancer and that it enhances c-Myc expression via the modulation of specific subsets of microRNAs. We discovered that USP2a localizes to early endosomes antagonizing EGFR endocytosis. This could be exploited therapeutically in cancers over-expressing EGFR.
Cell cycle regulation in cancer
We have been interested in the dissection of the pathways leading to altered cell cycle regulation in human solid tumors. We were the first to discover a tumor-specific proteolytic mechanism targeting p27 in colon tumors and establishing the loss of this cyclin-dependent kinase inhibitor as a powerful prognostic maker in many human cancers. More recently, we discovered a novel metabolic (“lipogenic”) G2/M checkpoint that can be exploited therapeutically.
Methods in molecular pathology to classify prostate cancer
We have developed, pioneered and disseminated several techniques in molecular pathology including multiplexed immunohistochemistry and in situ hybridization, de-convolution by spectral imaging and subsequent bioinformatics analysis, ex vivo tumor organotypic culture method to investigate antitumoral pharmacological properties that preserves the original cancer microenvironment, to the discovery of p63 as a diagnostic marker used in prostate cancer diagnosis, to the landscape of genomic alterations in prostate cancer as a co-leader of the Prostate TCGA Consortium and the molecular landscape of tumor stroma in prostate cancer.