Dissecting the role of mitochondrial dynamics in pancreatic carcinogenesis

Descripción del proyecto

La mitocondria como nueva diana contra el cáncer

El cáncer de páncreas supone un desafío médico significativo con un pronóstico funesto y mala respuesta a los tratamientos inmunitarios y los tratamientos convencionales. Esto indica claramente la necesidad de determinar los mecanismos responsables del inicio de la enfermedad y de identificar nuevas dianas que podrían utilizarse para un tratamiento temprano. El proyecto financiado con fondos europeos OPEN P-CAN investiga cómo la actividad mitocondrial potencia la carcinogénesis pancreática y cómo podemos aprovechar la biología de estos orgánulos para reducir la incidencia de la enfermedad. En concreto, el trabajo se centrará en el factor remodelador mitocondrial OPA1, un factor de pronóstico adverso para los pacientes de cáncer de páncreas, y en el potencial para atacarlo mediante métodos químicos y genéticos.

Objetivo

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.