Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022 PNRRRole of lactate as a metabolic regulator

Role of lactate as a metabolic regulator of ferroptosis sensitivity and metastatic dissemination in cancer cells

FPT is emerging as a new promising way to kill the most aggressive and therapy-resistant cancers. Yet many aspects of FPT remain poorly understood, precluding a rational approach to the design of FPT-based therapies. Cell metabolism is key for multiple cell functions, including cell death. This is especially true in the case of Ferroptosis (FPT), when cells die because of unrestrained accumulation of membrane phospholipid peroxides and radicals. Indeed, the production of radicals that initiate lipid peroxidation is thought to depend on essential metabolic functions such as oxidative phosphorylation, and their scavenging depends on metabolic pathways providing cells with reducing equivalents and antioxidants. Therefore, changes in nutrient availability or in metabolic pathways can influence FPT sensitivity.

This proposal aims at characterizing the mechanisms underlying the induction of FPT that occurs in primary and in metastatic cancer cells disseminating through the bloodstream towards distant organs, and how the primary tumor metabolic microenvironment affects the ability of invasive breast and prostate cancer cells to resist such metastasis-suppressor process. We found that lactic acid (LAC) produced by crowded breast cancer cells, or by cancer-associated fibroblasts (CAFs) present in the tumor microenvironment, is taken up by cancer cells themselves and confers protection from FPT induction. Altering the activity of LAC transporters in cancer cells can provide or prevent FPT protection, depending on the source of LAC (cancer cells or CAFs, respectively). Importantly, preconditioning cancer cells with LAC increases their dissemination efficiency to the lung in mice, similar to established FPT inhibitors, providing a new mechanism by which stromal cells or the tumor architecture can promote malignancy. Finally, we propose that blood-induced FPT may depend on neutrophils, which we found are able to kill cancer cells by FPT. We propose to characterize

how LAC-driven metabolic and transcriptional rewiring sets FPT resistance in cancer cells, and to study the interaction between cancer cells and neutrophils and its relevance for blood-induced FPT.

This project will advance our understanding of how tumor metabolism influences metastasis, and it will provide new mechanisms and targets for the future development of therapeutic approaches aimed at limiting metastatic dissemination of cancer cells. Moreover, our results may have implications for therapies based on inhibition of LAC transporters, which we find may increase metastatic ability. Finally, given the increasing realization that LAC is not only a metabolic waste, but also an important metabolic fuel, our studies might have implications to understand other phenomena, including for example metabolic cooperation between the hypoxic core and the vascularized periphery of solid tumors, or the protective exchange of LAC between cells in normal and diseased tissues.

 

Data di avvio 30 Novembre 2023

Data di completamento 30 Novembre 2025

Total cost  € 95000

 

Progetto P2022CE7SP finanziato all’interno del Bando PRIN 2022 PNRR di cui al Decreto Direttoriale n. 1409 del 14/9/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23033040001