Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by ¹⁸F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism.

中文翻译：

---

肌铁蛋白控制胰腺导管腺癌中线粒体的结构和活性，并影响肿瘤的侵袭性。

胰腺导管腺癌（PDAC）是与癌症相关的死亡的第三大主要原因。治疗选择仍然非常有限，并且基于经典的化学疗法。能量代谢重编程似乎是癌症的新兴标志，被认为是具有巨大潜力的治疗靶标。Myoferlin是在PDAC中过表达的Ferlin家族成员蛋白，与质膜生物学有关，具有促肿瘤作用。在我们先前研究的连续性中，我们研究了肌钙蛋白在PDAC能量代谢中的作用。我们使用选定的PDAC肿瘤样品和PDAC细胞系以及小干扰RNA技术来研究肌钙蛋白在能量代谢中的作用。在PDAC患者中，¹⁸ F-脱氧葡萄糖正电子发射断层扫描。我们发现，肌铁蛋白在脂肪生成的胰腺癌细胞系中更为丰富，是维持分支线粒体结构和高氧化磷酸化活性所必需的。观察到的由肌铁蛋白耗竭引起的线粒体裂变导致细胞增殖，ATP生成和自噬诱导减少，从而表明肌铁蛋白对于PDAC细胞适应性至关重要。肌铁蛋白沉默产生的代谢表型转换可以为治疗策略的发展开辟新的前景，特别是在能量代谢的情况下。