OPEN P-CAN · Dissecting the role of mitochondrial dynamics in pancreatic carcinogenesis

Dissecting the role of mitochondrial dynamics in pancreatic carcinogenesis

The proposal interrogated the role of mitochondrial dynamics in pancreatic cancer initiation and tested the hypothesis that oncogenic signaling drives changes in mitochondria to impact the nuclear epigenome. I had previously demonstrated that mitochondria-derived metabolites (i.e., acetyl-CoA) impact histone acetylation to facilitate pancreatic cancer onset. The research plan capitalized on the expertise of my mentor and project’s PI, Prof. Scorrano, whose work has pioneered the fields of mitochondria dynamics and inter-organelle communication. Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest human cancers. Overall, 5-year survival is approximately 9%; nearly 80% of patients present with unresectable and/or metastatic disease. With limited therapeutic options for advanced disease, public health benefits stand to be gained by improving our understanding of the factors that contribute to tumor onset with the hope of curtailing disease incidence. Mitochondria are intracellular organelles that serve critical bioenergetic and biosynthetic functions, but also influence nuclear chromatin. In particular, several studies indicate that histone acetylation is sensitive to mitochondrial activity. My central hypothesis was that mitochondrial structure is altered by KRAS signaling (aberrantly activated in PDA) and determines the relative risk for PDA. Specifically, aims of the project were: 1) Characterize the link between mitochondrial function and histone acetylation in pre-neoplastic cells 2) Dissect mitochondrial dynamics (change in number, morphology) during PDA initiation In brief, I found that that mitochondria exhibit tightening of inner membrane invaginations, termed cristae. This appear to be caused by upregulation of OPA1, a master regulator of cristae shape and biogenesis. Mouse models of OPA1 elevation show that cristae tightening is correlated with increased levels of histone acetylation and accelerated pancreatic carcinogenesis. Understanding how mitochondrial and epigenetic reprogramming facilitate oncogenesis bear the potential to unveil unprecedented opportunities for the prevention of the disease. In particular, I identified tighter mitochondrial cristae in pre-malignant cells; targeting OPA1 (or cristae biogenesis in general) becomes an attractive strategy to block tumor initiation. The Scorrano laboratory has recently developed an OPA1-specific inhibitor that showed the ability to restrain pancreatic acinar cell plasticity ex vivo, which correlates with anti-tumorigenic potential. Its effectiveness in vivo will be tested.

Data: CORDIS, © European Union