The molecular code of PTEN localization in tumor suppression; finanziato dall’Unione europea – Next Generation EU

Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN) is one of the most frequently lost or mutated tumor suppressor genes in human cancer and in a number of tumor syndromes, referred to as “PTEN hamartoma tumor syndromes” (PHTS). PTEN activity is historically associated with its phosphatase activity, but recent works have highlighted other differential activities generally referred to as non-canonical. It is fundamental to underline that PTEN activities, both canonical and non-canonical, have a great impact on cell function and metabolism including maintenance of genomic stability, cell survival, migration, and proliferation. Notably, PTEN has been shown to have differential localization within the cell. Besides its well-known nuclear and cytosolic localization, other organelles, such as the endoplasmic reticulum (ER), mitochondria, and mitochondria-associated membranes (MAMs), have been recognized as pivotal targets of PTEN activity. As stated before, it is well known that germline pathogenic PTEN mutations cause PHTS, but there are also cases in which PHTS are associated with wild-type PTEN, thus suggesting that PTEN might be affected also by modifications other than genetic alterations. These findings harbored the central hypothesis of this project, which is that PTEN might differentially contribute to the tumorigenic process according to its location, and its location might be defined by genetic or post-transcriptional modification. To unravel this hypothesis, the proposed work aims to i) characterize the differential PTEN localization according to its mutations both in in vitro cancer models and in human cancer tissues; ii) identify PTEN post-translational modifications and how they impact its subcellular localization; iii) evaluate how different PTEN localization affect its canonical and non-canonical functions. The identification of PTEN variations, both genetic or post-transcriptional, and of how these variations affect PTEN function will pave the wave to the identification of a novel prognostic and predictive biomarker, followed by the development of new possible target therapies.