Metabolic alterations in prostate cancer pathogenesis

Abstract

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs thatsustain cell growth, proliferation and promote cancer initiation and progression. In this thesis workwe describe a novel molecular mechanism by which mTORC1 regulates polyamine dynamics, ametabolic route that is essential for oncogenicity. Through the integrative metabolomics analysisof a mouse model and human biopsies of prostate cancer, we identified alterations in tumorsimpacting on the production of decarboxylated S-Adenosylmethionine (dcSAM) and polyaminesynthesis. Mechanistically, we demonstrate that this metabolic rewiring stems from mTORC1-mediated post-transcriptional control of S-Adenosylmethionine decarboxylase 1 (AMD1). Thisnovel molecular regulation was pharmacologically validated in samples from murine pre-clinicaland human clinical trials with Everolimus. Importantly, we demonstrate that manipulation of AMD1levels and activity dictates prostate cancer oncogenicity. The results in this thesis providefundamental information about the complex regulatory landscape controlled by mTORC1 tointegrate and translate growth signals into an oncogenic metabolic program.