Publication dans Redox Biology

Pharmacological targeting of myoferlin sensitizes pancreatic cancer cells to ferroptosis


The Metastasis Research Laboratory, co-headed by Olivier Peulen and Akeila Bellahcène (GIGA-Cancer and CIRM), has been studying the myoferlin protein and its role in pancreatic cancer for many years. Their efforts have led to the discovery that pharmacological targeting of this protein induces cancer cell death by iron accumulation. This accumulation also sensitises these cells to other inducers of ferroptosis. Research recently published in Redox Biology.

Pancreatic cancer is one of the deadliest forms of cancer and its incidence is increasing. Usually undetected at an early stage, it is often diagnosed at an advanced stage. This late diagnosis contributes to one of the lowest survival rates, with a median survival of only a few months. Treatment options are still very limited and often rely on conventional chemotherapies that are difficult to tolerate and only modestly increase survival. It is therefore crucial to find early detection strategies and innovative therapeutic targets to develop an effective treatment. It is in this context that myoferlin has been considered, since 2011 by the Metastasis Research Laboratory, as a biomarker for pancreatic cancer.

Researchers at the Metastasis Research Laboratory have discovered that this protein, physiologically involved in membrane biology, has a tumour-promoting function that has not been fully understood. The in-depth study of this function now allows them to consider myoferlin as a potential therapeutic target.

Research at the Metastasis Research Laboratory has previously suggested a link between myoferlin and the function of mitochondria in pancreatic cancer cells. Further investigation of this link allowed Gilles Rademaker and Yasmine Boumahd, working under the supervision of Olivier Peulen, to observe that a small molecule binding to myoferlin was toxic to the cancer cells and caused destruction of their mitochondrial network. They also showed that this observation was accompanied by a specific degradation of mitochondria, mitophagy, and by an accumulation of reactive oxygen species in the cytoplasm. In an attempt to understand the origin of these reactive oxygen species, they demonstrated that the intracellular iron concentration increased a few hours after targeting the myoferlin. This increase in iron concentration was responsible for the formation of reactive oxygen species and for the cytotoxic effects of pharmacological targeting of myoferlin. The researchers then sought to better understand the reasons that led to the death of the cancer cells. It appeared that the cancer cell could not activate a defense system against reactive oxygen species, resulting in damage to the cell membranes. The cells thus underwent ferroptosis. Inspired by this discovery, the research team combined the pharmacological agent directed against myoferlin with molecules (erastin, RSL3) whose analogues (e.g. PRLX93936) are currently in the clinical trials. They have shown that there is synergy between the different molecules and that it is therefore possible to envisage more effective treatments or treatments using lower concentrations, thus limiting possible side effects.

These results open up interesting therapeutic perspectives but nevertheless require several verifications, including in models closer to the patient.


Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells.

Rademaker, G. et al.  Redox Biol 102324 (2022) doi:10.1016/j.redox.2022.102324.



Olivier Peulen

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