Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Is NRF2-driven metabolic reprogramming

Is NRF2-driven metabolic reprogramming a unique feature of cancer cells? A study on normal, preneoplastic and neoplastic hepatocytes.

Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. Insofar, the definition of metabolic reprogramming has been applied to cancer cells. However, whether metabolic reprogramming is a unique property of neoplastic cells or can take place also in normal proliferating cells is unclear since some of the metabolic dependencies of neoplastic cells have been observed in normal cells undergoing replication. Unfortunately, as no systematic studies have been performed, whether also normal cells, can, under certain conditions, undergo the same metabolic reprogramming of cancer cells remains an open question.

The nuclear factor erythroid-derived 2-like 2 (Nrf2) transcription factor mediates proliferation and metabolic reprogramming in tumor cells, including hepatocellular carcinoma (HCC), one of the most lethal cancers worldwide. Although metabolic reprogramming is crucial for the process of hepatocarcinogenesis, our preliminary data suggest that hepatocyte proliferation induced in normal liver by some chemicals endowed with mitogenic activity is Nrf2-dependent and promotes a metabolic rewiring with features comparable to those observed in hepatic preneoplastic lesions and HCC. This raises the question as to whether Nrf2 activation in normal hepatocytes is capable of inducing a metabolic reprogramming identical to that observed in cancer cells. Comparison of metabolic profiling of normal, pre-, and neoplastic hepatocytes might represent an important perspective to elucidate the critical changes underlying HCC progression and discriminate the reversible changes from those required for sustaining the carcinogenic process. This in turn may lead to the improvement of existing therapeutic strategies aimed at targeting metabolic pathways.

Based on these premises, we will:

1. establish whether metabolic reprogramming can occur in normal proliferating hepatocytes and gain a comprehensive knowledge of the metabolic features induced by mitogenic stimuli using transcriptomic and metabolomic analysis;

2. describe the metabolic features exhibited by pre- and neoplastic hepatocytes generated by a multi-step model of hepatocarcinogenesis;

3. compare the metabolic reprogramming that sustains normal proliferating hepatocytes with that found in pre- and neoplastic hepatocytes to identify the features exclusively associated with cancer, with a focus on the role of Nrf2. These aims will be addressed by integrating the complementary expertise of 2 research Units

(UniCA and UniFI) that have an established and long-lasting collaboration: UniCA will coordinate the execution of the project, develop in vivo experimental models and perform the transcriptomic analysis. UniFI will perform the functional metabolic and metabolomic analysis of the described models and perform the molecular and metabolic analysis of the in vitro models.

 

Data di avvio 18 Ottobre 2023

Data di completamento 18 Ottobre 2025

Total cost  €118077,00

 

Progetto 2022RCFZZ3 finanziato all’interno del Bando PRIN 2022 di cui al Decreto Direttoriale n. 104 del 02/02/2022 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 B53D23021880006