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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 detailMetastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis.
Chiavarina, Barbara; Costanza, Brunella ULiege; Ronca, Roberto et al

in Theranostics (2021), 11(4), 1626-1640

Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via ... [more ▼]

Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo. Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo, underscoring its diagnostic and therapeutic potential. Conclusions: TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies. [less ▲]

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See detailTumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.
Luis, Géraldine; Godfroid, Adrien; Nishiumi, Shin et al

in Redox Biology (2021), 43

PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and ... [more ▼]

PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. METHODS: Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. RESULTS: We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic - or by pharmacological - targeting SCD1 in vivo, tumor regrowth was abolished completely. CONCLUSION: This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence. [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 detailDicarbonyl stress induces an epigenetic deregulation leading to a pro-migratory phenotype in breast cancer.
Tiamiou, Assia ULiege; Dube, Gaurav; Bizet, Martin et al

Poster (2020, February 07)

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See detailMethylglyoxal stress contributes to immunosuppression in breast cancer
Wissocq, Tom ULiege; Hubert, Pascale ULiege; Caprasse, Maurine ULiege et al

Poster (2020, February 07)

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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 detailRole of myoferlin in mitochondrial dynamics and metabolic fitness of Pancreatic Ductal Adenocarcinoma
Anania, Sandy ULiege; Rademaker, Gilles ULiege; Bellahcene, Akeila ULiege et al

Poster (2019, December)

Pancreatic cancer is the 7th most common cause of cancer mortality in the world. It is predicted to become the 2nd leading cause of cancer-related death in 2030. In the majority of cases, due to a late ... [more ▼]

Pancreatic cancer is the 7th most common cause of cancer mortality in the world. It is predicted to become the 2nd leading cause of cancer-related death in 2030. In the majority of cases, due to a late diagnosis, the tumor is not resectable and already disseminated. Therefore, new specific biomarkers providing early diagnosis for pancreatic cancer are needed. In addition to the lack of specific and early biomarkers, chemotherapies (gemcitabine and folfirinox) poorly improve the overall survival of Pancreatic Ductal Adenocarcinoma (PDAC) patients. Hence, a better understanding of physiopathological processes underlying PDAC is required in order to offer more effective treatments. Myoferlin is a 230 kDa protein with multiple C2 domains known to interact, through calcium binding, with negatively charged phospholipids. This protein was first described in myoblast fusion. Interestingly, Myoferlin is also overexpressed in several cancers, including pancreatic cancer, where it plays a role in endocytosis, exocytosis, and has been located in exosomes. Recently, our team showed a fragmentation of the mitochondrial network in PDAC cells when myoferlin was depleted using siRNA. Understanding the mechanism underlying this mitochondrial disruption would be of great interest as mitochondria are major actors in cancer development, progression and resistance. Owing to the known role of myoferlin in membrane fusion, we assessed its direct involvement in the mitochondrial fusion machinery. Indeed, if myoferlin is a part of the mitochondrial fusion machinery, its silencing together with an unopposed fission would lead to mitochondrial fragmentation. First, we performed immunofluorescence to colocalize myoferlin and a mitochondrial outer membrane 65kDa protein. Colocalization studies showed no significant colocalization. We then performed immunofluorescence to stained myoferlin and the main factor of mitochondrial fusion mitofusin-1/2 (MFN1/2). Colocalization image analysis revealed a 60% colocalization between both proteins. Those results were further confirmed by PLA (Proximity Ligation Assay). Finally, to evaluate a direct protein-protein interaction, we performed a co-immunoprecipitation assay. The main isoform of myoferlin appeared to coimmunoprecipitate with MFN1/2, suggesting a direct interaction between these proteins. [less ▲]

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See detailRole of myoferlin in mitochondrial dynamics and metabolic fitness of PDAC
Anania, Sandy ULiege; Rademaker, Gilles ULiege; Wissocq, Tom ULiege et al

Poster (2019, October)

Our data strongly suggest that myoferlin interacts with MFN. Indeed, if myoferlin is a part of the mitochondrial fusion machinery, its silencing together with an unopposed fission would lead to ... [more ▼]

Our data strongly suggest that myoferlin interacts with MFN. Indeed, if myoferlin is a part of the mitochondrial fusion machinery, its silencing together with an unopposed fission would lead to mitochondrial fragmentation. [less ▲]

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See detailRole of myoferlin in mitochondrial dynamics and metabolic fitness of pancreas cancer
Anania, Sandy ULiege; Rademaker, Gilles ULiege; Wissocq, Tom ULiege et al

Poster (2019, September 06)

Pancreatic cancer is the 7th most common cause of cancer mortality in the world. It is predicted to become the second leading cause of cancer-related death in 2030. Myoferlin is a 230 kDa protein ... [more ▼]

Pancreatic cancer is the 7th most common cause of cancer mortality in the world. It is predicted to become the second leading cause of cancer-related death in 2030. Myoferlin is a 230 kDa protein overexpressed in pancreatic cancer. Recently, our team showed a fragmentation of the mitochondrial network in PDAC cells when myoferlin was depleted using siRNA. Understanding the mechanism underlying this mitochondrial disruption would be of great interest as mitochondria are major actors in cancer development, progression and resistance [less ▲]

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See detailFerlin overview: from membrane to cancer biology
Peulen, Olivier ULiege; Rademaker, Gilles ULiege; Anania, Sandy ULiege et al

in Cells (2019), 8

In mammal myocytes, endothelial cells, and inner ear cells, ferlins are proteins involved in membrane processes such as fusion, recycling, endo- and exocytosis. They harbour several C2 domains allowing ... [more ▼]

In mammal myocytes, endothelial cells, and inner ear cells, ferlins are proteins involved in membrane processes such as fusion, recycling, endo- and exocytosis. They harbour several C2 domains allowing their interaction with phospholipids. Membrane biology is of extreme importance for cell survival and signalling, making Ferlin proteins core machinery indispensable for cancer cell adaptation to hostile environment. Expression of several Ferlin genes was described as altered in several cancer types. Among them myoferlin was recently discovered as highly expressed in several tumoural tissues, and negatively correlated to patient survival. Evidences suggest that myoferlin, when overexpressed, enhances cancer cell proliferation, migration and metabolism by affecting various aspects of membrane biology. Targeting myoferlin using pharmacological compounds, gene transfer technology, or interfering RNA is now considered as an emerging therapeutic strategy. [less ▲]

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See detailA novel link between dicarbonyl stress and epigenetic regulation in breast cancer
Tiamiou, Assia ULiege; Dube, Gaurav; Bizet, Martin et al

Poster (2019, June 13)

Detailed reference viewed: 21 (2 ULiège)