Myoferlin Contributes to the Metastatic Phenotype of Pancreatic Cancer Cells by Enhancing Their Migratory Capacity through the Control of Oxidative Phosphorylation

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with an overall survival of 5% and is the second cause of death by cancer, mainly linked to its high metastatic aggressiveness. Accordingly, understanding the mechanisms sustaining the PDAC metastatic phenotype remains a priority. In this study, we generated and used a murine in vivo model to select clones from the human Panc-1 PDAC cell line that exhibit a high propensity to seed and metastasize into the liver. We showed that myoferlin, a protein previously reported to be overexpressed in PDAC, is significantly involved in the migratory abilities of the selected cells. We first report that highly metastatic Panc-1 clones expressed a significantly higher myoferlin level than the corresponding low metastatic ones. Using scratch wound and Boyden’s chamber assays, we show that cells expressing a high myoferlin level have higher migratory potential than cells characterized by a low myoferlin abundance. Moreover, we demonstrate that myoferlin silencing leads to a migration decrease associated with a reduction of mitochondrial respiration. Since mitochondrial oxidative phosphorylation has been shown to be implicated in the tumor progression and dissemination, our data identify myoferlin as a valid potential therapeutic target in PDAC.

Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells

“…In cancer, an increasing body of literature links mitochondrial fusion/fission to cancer cell metabolism [24,25]. Apparently discordant results concerning functional impact of mitochondrial fusion/fission [2][3][4] suggest that disturbing mitochondrial dynamics is more important than specifically inhibiting fusion or fission [5].…”

“…Conversely, we previously showed in PDAC cell lines that a mitochondrial fission was associated with OXPHOS decrease, and enhanced autophagy [4]. Interestingly, in a mice model, a lower metastatic potential of PDAC cells was associated with a reduced OXPHOS [2]. Consequently, it appeared more important to disturb mitochondrial dynamics rather than to specifically inhibit fusion or fission [5].…”

“…Pancreas ductal adenocarcinoma (PDAC) is one of the deadliest diseases with a 5-year survival lower than 10%. In PDAC, mitochondria activity was described to be involved in tumor relapse [1] and in metastatic dissemination [2]. Mitochondria are highly dynamic structures oscillating from a branched network to individual organelles according to the metabolic needs or mitochondrial damages.…”

Cancer and pH Dynamics: Transcriptional Regulation, Proteostasis, and the Need for New Molecular Tools

“…Many pHi-dependent tumorigenic behaviors, such as proliferation, epithelial-to-mesenchymal transition (EMT), and metabolic reprogramming have been shown to be driven by proteostatic changes. For example, stabilization of the oncogene Myoferlin [ 84 ] enables tumor growth and angiogenesis through VEGF-secretion in pancreatic cancer [ 85 ], promotes migration and EMT through epidermal growth factor receptor (EGFR) recycling in breast cancer [ 86 ] and supports oxidative phosphorylation by retaining mitochondrial integrity in colon cancer [ 87 ]. Additionally, the transcriptional regulator bromodomain-containing protein 4 (BRD4) had an increased abundance in colon cancer that promoted growth and invasion independently of its transcriptional targets, Myc and B-cell lymphoma 2 (BCL2), by stabilizing acetylated Snail and promoting proliferation through a post-translational regulatory mechanism [ 88 ].…”

Extracellular Vesicles (EVs) and Pancreatic Cancer: From the Role of EVs to the Interference with EV-Mediated Reciprocal Communication

“…Myoferlin regulates multiple biologic events, such as endocytosis and membrane repair/fusion. In pancreatic cancer cells, myoferlin is noticed to maintain the structure and activity of mitochondria, thereby enhancing the growth and migration of cancer cells [101,102]. In addition, myoferlin can protect the Cbl-induced proteasomal degradation of VEGF receptor 2 (VEGFR2) in ECs [103].…”