Abstract :
[en] In 2020, globally, the total number of new pancreatic cancer (PDAC) cases was around 500,000, and the total number of deaths from pancreatic cancer was 470,000. This context led our Laboratory to highlight new PDAC biomarkers. Myoferlin is a protein involved in membrane fusion and membrane receptor recycling. In 2011, the Metastasis Research Laboratory was among the first to demonstrate myoferlin's protein overexpression in PDAC, necessary for optimal cancer cell growth. The Metastasis Research Laboratory's work subsequently demonstrated a link between myoferlin and the function of pancreatic cancer cell mitochondria. Recently, we then took advantage of a myoferlin pharmacological inhibitor (WJ460) synthetized by Zhang et al. targeting its C2D domain to test its effects on different PDAC lines and a healthy pancreatic cell line. We reproduced the main effects raised by myoferlin siRNA transfection in PDAC cell lines, such as mitochondrial network destruction, total reactive oxygen species (ROS) accumulation, and reduced oxidative phosphorylation under WJ460. We also showed these observations were accompanied by a specific mitochondria degradation, mitophagy. Also, myoferlin targeting induced an accumulation of cytoplasmic iron concentration. This iron increase resulted from the release of iron storage from degraded mitochondria and induced the accumulation of total ROS in the cytoplasm via the Fenton reaction resulting in a specific cell death process known as ferroptosis. Finally, we demonstrated that altering the mitochondrial oxidative balance sensitized pancreatic cancer cells to radiotherapy via total ROS production inducing DNA damage. Indeed, simultaneous treatment with WJ460 and irradiation induced a synergy in several pancreatic cancer lines. Moreover, we concluded that the effect was specific to cancer cells, with little to no effect on the healthy cell line. As myoferlin is not expressed in most healthy organs, targeting myoferlin is of particular interest. This suggests therapies targeting myoferlin could be specific to diseased cells without affecting healthy tissues, reducing undesirable side effects. We believe we have revealed a cell vulnerability that can be exploited in patient treatment. Indeed, this study identified myoferlin as a potential biomarker of PDAC radio-resistance
