Myoferlin at the crossroad of vesicle trafficking and mitochondrial function: implications for pancreatic cancer progression and stromal reprogramming.

Myoferlin, a type 2 transmembrane protein in the ferlin family, is traditionally known for its role in membrane fusion during muscle development and repair. Recent research identifies myoferlin as a potential biomarker and a critical driver of cancer progression, particularly in breast cancer and pancreatic ductal adenocarcinoma. While its lack of specificity limits its use as a biomarker, its multifaceted role in cellular membrane dynamics makes it a promising therapeutic target. In cancer cells, myoferlin regulates the recycling and stability of receptor tyrosine kinases, thereby promoting invasion and metastasis. Beyond the plasma membrane, it maintains mitochondrial homeostasis by interacting with the machinery for mitochondrial fusion and calcium exchange at the endoplasmic reticulum-mitochondria interface. Depletion of myoferlin disrupts these processes, leading to mitochondrial fragmentation, reduced ATP production, and iron-dependent cell death. Furthermore, myoferlin influences the tumour microenvironment by regulating pancreatic cancer-associated fibroblasts. It interacts with SEC24 to facilitate the coat protein complex II-mediated transport of the transforming growth factor-beta 1 receptor, driving the desmoplastic reaction and matrix protein deposition. The 'one punch-two hits' strategy-simultaneously targeting the metabolic and signalling pathways of both malignant cells and the stroma-offers a novel therapeutic perspective. The development of small molecules targeting myoferlin's C2 domains confirms its potential to reduce tumour growth and metastatic dissemination.