"We aim at unravelling the secrets of autophagy, a process of cell survival involved in stress response and cell cycle regulation. The success of a cancer cell highly depends on autophagy ....".
Professor Francesco Cecconi
Autophagy is a highly conserved catabolic process, by which cytoplasmic material (e.g., proteins, lipids and organelles) is transported to lysosomes for degradation by means of double-membraned vesicles, the autophagosomes.
Its importance in a vast range of diseases has been postulated, including disorders of the immune system, cancer and neurodegeneration.
However, although the main pathways of autophagy have been elucidated at a deep molecular level, the relative importance of this process in controlling the switch between death and survival, the rate of cell growth and the regulation of cell differentiation, all need more investigation.
Our Lab is committed to unravelling the upstream regulation of autophagy and elucidating the role of this process in cancer. In cancer, autophagy may serve as a barrier to limit tumour initiation and as an adaptive response functional to malignant progression in the established neoplastic lesions. In addition to ties to the tumorigenesis, there is also evidence for a direct role for autophagy in controlling cell proliferation and vice versa, but less is known about this relationship. In this context, in our lab we are studying the function of the pro-autophagic protein AMBRA1 in cell cycle regulation and its implications in tumour insurgence.
In another line of research, we focus on the role of S-nitrosylation and GSNOR-mediated denitrosylation reactions in cancer development and progression. Indeed, although less and conflicting data support the role of NO and NO synthase in tumorigenesis, very recently it has been demonstrated that GSNOR-deficient mice spontaneously develop hepatocellular carcinoma (HCC) and that in human HCC patients, the GSNOR gene is mutated or partially deleted, leading to defect of the DNA repair system.
However, since the total absence of DNA repair enzymes defective in GSNOR-deficient conditions is not sufficient per se to induce HCC, it is reasonable that other S-nitrosylation-responsive mechanisms/processes should be involved in HCC onset. In this context, mitochondria have been reported being a preferential target of S-nitrosylation, and therefore we are studying in vitro and in vivo the role of GSNOR in regulating mitochondrial energetics, dynamics and removal by autophagy (the so-called mitophagy) as additional mechanisms whose impairment, induced by GSNOR ablation or reduction, can result in neoplastic transformation.
Moreover, we are also investigating how alterations in these processes impact on tumour metabolic reprogramming and redox adaptations, so as to find the Achilles heel of GSNOR-deficient tumours and, in turn, to activate alternative cell death pathways aimed at the their complete eradication.