Dissecting the role of mitochondrial dynamics in pancreatic carcinogenesis

Descrizione del progetto

I mitocondri come nuovo bersaglio antitumorale

Il cancro al pancreas rappresenta una sfida medica significativa con una prognosi sfavorevole e una risposta povera alle terapie convenzionali e immunologiche. Ciò indica chiaramente la necessità di determinare i meccanismi responsabili dell’insorgenza della malattia e identificare nuovi bersagli che possano essere sfruttati molto prima per il trattamento. Il progetto OPEN P-CAN, finanziato dall’UE, sta investigando il modo in cui l’attività mitocondriale supporta la carcinogenesi pancreatica e come è possibile sfruttare la biologia degli organuli per ridimensionare l’incidenza della malattia. In particolare, il lavoro si concentrerà sul fattore di rimodellamento dei mitocondri OPA1, un fattore prognostico sfavorevole per i pazienti affetti da cancro pancreatico, e sul potenziale per affrontarlo attraverso approcci genetici e chimici.

Obiettivo

OPA1 Educates the Nucleus in Pancreatic CANcer. Pancreatic cancer represents an unresolved health burden, showing abysmal chances of survival and refractoriness to conventional and immunological therapies. Significant benefit will be gained from a better understanding of molecular mechanisms leading to cancer formation, with the goal to curtail disease incidence and improve the opportunities to treat it early. The study will describe how mitochondria and nuclei communicate to facilitate pancreatic cancer initiation. Building from my prior research in metabolic-dependent histone acetylation, and leveraging on the host laboratory expertise in mitochondrial dynamics, I designed a roadmap for the study of how mitochondrial activity is altered during pancreatic carcinogenesis and whether that can be exploited for therapeutic purposes. I will decipher the specific role of major cristae-remodeling factor OPA1, which is an unfavorable prognostic factor for pancreatic cancer patients. I will seek how OPA1-altered expression impacts mitochondrial function and metabolite availability in mouse pre-malignant cells, using in vivo models of pancreatic carcinogenesis. My previous experimentation found that metabolite-dependent histone acetylation is critical for the initiation of pancreatic carcinogenesis. I will now investigate whether OPA1-mediated mitochondrial rewiring impacts citrate and acetyl-CoA abundance in a way that alters the levels of histone acetylation. Epigenetic reprogramming will be further investigated in various OPA1 transgenic mice. Finally, the therapeutic potential of OPA1 targeting will be addressed using both genetic and chemical approaches using resources recently developed at the host laboratory. The project represents a career-defying framework for the study of molecular determinants of pancreatic cancer onset.