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See detailMyoferlin, a promising therapeutic target in PDAC, is located in mitochondria-associated membranes
Anania, Sandy ULiege; Boumahd, Yasmine ULiege; Peiffer, Raphaël ULiege et al

Poster (2021, June)

Pancreatic cancer has one of the lowest survival rates with more than 90% of patients dying of the disease. It is predicted that pancreatic cancer will surpass breast cancer death by 2025. Therefore ... [more ▼]

Pancreatic cancer has one of the lowest survival rates with more than 90% of patients dying of the disease. It is predicted that pancreatic cancer will surpass breast cancer death by 2025. Therefore, finding new therapeutic strategies is of major importance. Recently, myoferlin, a protein overexpressed in pancreatic cancer, has been shown to impact mitochondrial dynamics and respiration. Because myoferlin has been showed to be a potential therapeutic target in PDAC, understanding its function and determining its localization in PDAC is of major importance. We focused our interest on mitochondria-associated membranes (MAMs). [less ▲]

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See detailMyoferlin is a yet unknown interactor of the mitochondrial dynamics’ machinery in pancreas cancer cells
Anania, Sandy ULiege; Peiffer, Raphaël ULiege; Rademaker, Gilles ULiege et al

in Cancers (2020), 12(6), 1643

Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types ... [more ▼]

Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, and demonstrated that myoferlin depletion disturbs the mitochondrial dynamics culminating to a mitochondrial fission. In order to unravel the mechanism underlying this observation, we explored the myoferlin localization in pancreatic cancer cells and showed a colocalization with the mitochondrial dynamic machinery element: mitofusin. This colocalization was confirmed in several pancreas cancer cell lines and in normal cell lines as well. Moreover, in pancreas cancer cell lines, it appeared that myoferlin interacted with mitofusin. These discoveries open-up new research avenue aiming at modulating mitofusin function in pancreas cancer. [less ▲]

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See detailMethylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
Bellier, Justine ULiege; Nokin, Marie-Julie ULiege; Caprasse, Maurine ULiege et al

in Cell Reports (2020), 30(5), 1400-14166

The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been ... [more ▼]

The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC. [less ▲]

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See detailMyoferlin contributes to the metastatic phenotype of pancreatic cancer cells by enhancing their migratory capacity through the control of oxidative phosphorylation
Rademaker, Gilles ULiege; Costanza, Brunella ULiege; Anania, Sandy ULiege et al

in Cancers (2019), 11(6),

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 ... [more ▼]

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 have 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 metastasized 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 PANC-1 metastatic clones expressed significantly higher myoferlin level than the corresponding low metastatic ones. Using scratch wound and Boyden’s chamber assays, we show that cells expressing 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 to 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. [less ▲]

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See detailHuman colon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis.
Rademaker, Gilles ULiege; Costanza, Brunella ULiege; Bellier, Justine ULiege et al

in Oncogenesis (2019)

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use ... [more ▼]

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use of glycolysis to produce energy. Recent studies demonstrated that mitochondrial electron transport chain inhibitor reduced colon cancer tumour growth. Accumulating evidence show that myoferlin, a member of the ferlin family, is highly expressed in several cancer types, where it acts as a tumour-promoter and participates in the metabolic rewiring towards oxidative metabolism. In this study, we showed that myoferlin expression in colon cancer lesions is associated with low patient survival and is higher than in non-tumoural adjacent tissue. Human colon cancer cells silenced for myoferlin exhibit a reduced oxidative phosphorylation activity associated with mitochondrial fission leading, ROS accumulation, decreased cell growth, and increased apoptosis. We observed the triggering of a DNA damage response culminating to a cell cycle arrest in wild-type p53 cells. The use of a p53 null cell line or a compound able to restore p53 activity (Prima-1) reverted the effects induced by myoferlin silencing, confirming the involvement of p53. The recent identification of a compound interacting with a myoferlin C2 domain and bearing anti-cancer potency identifies, together with our demonstration, this protein as a suitable new therapeutic target in colon cancer. [less ▲]

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