Lactate signalling in chemoresistance: from a potential threat to a therapeutic opportunity.

Cancer cells are characterized by high glucose consumption, leading to increased lactate production. Once considered a waste product, lactate was recently shown to take part in the epigenetic regulation of gene expression, in promoting the unlimited growth of cancer cells and in facilitating metastasis. Furthermore, aberrant metabolism of cancer cells emerged as significant factor affecting drug efficacy and several evidences correlated some therapeutic failures with changes in cell metabolic asset. My Ph.D. project is focused at characterizing the effects of lactate signalling in cancer cells, with special attention to the potential role of this metabolite in modifying the response of cancer cells to chemotherapeutic treatments and in promoting the onset of drug resistance. In particular, this thesis describes how lactate influences the response of cancer cells to some commonly used chemotherapeutic drugs, such us cisplatin, doxorubicin and tamoxifen, while also highlighting the potential role of lactate in promoting the activated state of the EGFR receptor. The investigation was conducted using different cancer cell lines, with special attention on colon and breast adenocarcinomas. Overall, the described experiments have elucidated that lactate can induce drug resistance through pathways that may differ according to cancer cell histology. In agreement with our findings, it would be essential to develop strategies to obtain the inhibition of lactate production. A direct way for achieving this goal is through the inhibition of LDHA, the primary enzyme isoform responsible for lactate production in cancer cells. In this context, I collaborated in a study coordinated by Professors Alejandro Hochkoeppler and Luca Gentilucci, (University of Bologna) who designed peptides with potential inhibition on LDHA activity. The conclusive section of this thesis describes experiments aimed at evaluating the efficacy of these peptides in cancer cell cultures.