Over the past decade a large body of work has demonstrated that oncogenes and tumor suppressors play a key role in regulating the metabolic transformation of cancer cells and in directing the use of glucose, glutamine, and other nutrients to the generation of lipids, nucleic acids, and proteins for dividing cells. Mitochondria are key actors in the metabolic reprogramming of cancer cells, and several oncogenes and tumor suppressors exert their metabolic function via modulation of mitochondrial processes. The key role of mitochondria in cancer is further corroborated by the finding that mitochondrial enzymes, when mutated, can predispose to hereditary and sporadic forms of cancer. For instance, mutations of the mitochondrial housekeeping genes such as succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase-2 were identified in different types of cancer, suggesting that, in some circumstances, mitochondrial dysfunction sufficient to drive tumorigenesis. Two of these genes, SDH and FH, are classified as tumor suppressors, as affected individuals inherit one mutated copy of the relevant gene, whereas the tumors exhibit loss of the wild-type allele following a somatic ‘second event’ in keeping with Knudson’s classic two-hit hypothesis. Additionally, a recent bulk of evidence points to a role for mutations in mtDNA in driving cancer progression and adaptation, indicating that respiratory complex proteins, which are also metabolic enzymes, have a full potential to be annotated as tumor suppressors or oncogenes, or even play a double-edged role according to the type and load of mutations. Investigations of the mechanisms of action of mitochondrial defective enzymes ultimately revealed new players in the field of oncology, namely the oncometabolites, i.e. small metabolites, such as fumarate and succinate, that, when accumulated as a consequence of mitochondrial dysfunction, induce profound genetic and epigenetics changes that predispose to cancer cell transformation. Indeed, a mechanistic gap exists between the finding of cancer-associated genetic lesions and tumor progression, which this WP intends to fill in with an in-depth investigation of the regulators and pathways which are activated following mutations in metabolic enzymes, and that ultimately lead to a pro-tumorigenic metabolic rewiring. To this aim, UCAM will investigate how the loss of the mitochondrial tumor suppressor FH predisposes to cancer transformation. UNIBO will dissect how respiratory complex I (CI) can modulate metabolic and hypoxia adaptation. KI will tackle how mitochondrial biogenesis regulators, upstream of metabolic enzymes, may impact on cancer progression and adaptation. Lastly, BIOCRATES will improve different technologies to determine the contribution of cofactors in cancer metabolic reprogramming.

One of the encountered hurdles in treatment of cancer is the partial or complete resistance of certain tumors to conventional therapeutic interventions. Furthermore, it is well accepted that cancer manifests into many types, depending on the tissue affected, and that both environmental and genetic factors influence the metabolic, hypoxic and vascularization features of this disease. Thus, one of the most important challenges in medicine is the development of novel and more effective therapies to improve survival of cancer patients. The peculiar metabolic profile of cancer may be an ideal target for therapeutic interventions that selectively hit cancer cells with minimal residual systemic toxicity. Within TRAMSMIT we will attempt to understand the mechanisms leading to altered tumor cell metabolism and its consequences to open up new therapeutic windows for the treatment of cancer. The majority of studies targeting cancer metabolism aims to inhibit several steps of glycolysis. So far, less explored options to interfere with mitochondrial metabolism as adjuvant therapy will be the focus of the translational WP of TRANSMIT. First of all, ACS will generate 3D cell models that recapitulate the metabolic changes leading to malignant transformation, which offer potential targets for therapeutic intervention. Recent studies on administration of biguanides, a new class of CI inhibitors, pointed out that druggability of CI function may represent a promising strategy for the urgency of new treatments for cancer. Further, treatment of melanomas with CI inhibitors and Vemurafenib elevates the anti-neoplastic potential of this BRAF-targeted drug. UNIBO will address the issue of the efficacy of pharmacological strategies either targeting CI or its downstream pathways involved in the hypoxia-driven response. UCL will be engaged in the dissection and targeting of the signaling pathways activated by mitochondrial reactive oxygen species (mtROS) and involved in the promotion of tumor metastasis. Finally, SALK will directly target the increased glycolysis and low OXPHOS activity by dietary intervention. Due to the metabolic adaptability of cancer cells, it may be necessary to combine agents that target different metabolic pathways to achieve high therapeutic efficacy. Targeting of metabolic reprogramming in cancer cells should render them more sensitive to classical chemo or radiation therapy and would likely permit reduced drug doses or duration of treatment.