Le ciblage de la myoferline induit la mitophagie et amorce la ferroptose dans les cellules cancéreuses pancréatiques

peer reviewe

Methylglyoxal: a novel upstream regulator of DNA methylation.

peer reviewed[en] BACKGROUND: Aerobic glycolysis, also known as the Warburg effect, is predominantly upregulated in a variety of solid tumors, including breast cancer. We have previously reported that methylglyoxal (MG), a very reactive by-product of glycolysis, unexpectedly enhanced the metastatic potential in triple negative breast cancer (TNBC) cells. MG and MG-derived glycation products have been associated with various diseases, such as diabetes, neurodegenerative disorders, and cancer. Glyoxalase 1 (GLO1) exerts an anti-glycation defense by detoxifying MG to D-lactate. METHODS: Here, we used our validated model consisting of stable GLO1 depletion to induce MG stress in TNBC cells. Using genome-scale DNA methylation analysis, we report that this condition resulted in DNA hypermethylation in TNBC cells and xenografts. RESULTS: GLO1-depleted breast cancer cells showed elevated expression of DNMT3B methyltransferase and significant loss of metastasis-related tumor suppressor genes, as assessed using integrated analysis of methylome and transcriptome data. Interestingly, MG scavengers revealed to be as potent as typical DNA demethylating agents at triggering the re-expression of representative silenced genes. Importantly, we delineated an epigenomic MG signature that effectively stratified TNBC patients based on survival. CONCLUSION: This study emphasizes the importance of MG oncometabolite, occurring downstream of the Warburg effect, as a novel epigenetic regulator and proposes MG scavengers to reverse altered patterns of gene expression in TNBC

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

Myoferlin, an emerging oncoprotein, has been associated with a low survival in several cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated cancer cells to iron-dependent cell death, ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death. WJ460 caused a reduction of the abundance of ferroptosis core regulators xc- cystine/glutamate transporter and GPX-4. Mitophagy inhibitor Mdivi1 and iron chelators inhibited the myoferlin-related ROS production and restored cell growth. Additionally, we reported a synergic effect between ferroptosis inducers, erastin and RSL3, and WJ460

Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic CancerCancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer

Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies

Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer

Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies

Modulation de la radiosensibilité des cellules pancréatiques cancéreuses par le ciblage pharmacologique de la myoferline.

Pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related deaths by 2030. Myoferlin is a protein involved in membrane fusion and in membrane receptors recycling and is overexpressed in PDAC where it was reported to be required for an optimal cell growth. We used an innovative small compound (WJ460) to target myoferlin in PDAC cell lines and reported the triggering of ferroptosis, involving mitochondrial iron pool. Based on those results, we believe we revealed a pancreatic cell vulnerability that can be exploited in the treatment of patients with PDAC. Indeed, the alteration of the mitochondrial redox balance is a pathway followed to sensitize cancer cells to radiotherapy. Radiotherapy alone or combined with chemotherapy is a therapeutic modality of the PDAC. Our working hypothesis is that inhibition of myoferlin function sensitizes PDAC cancer cells to radiotherapy. A preliminary analysis carried out using the MiaPaCa-2 cell line demonstrated a significative synergy between WJ460 and irradiation for different combinations. With the aim if increasing the clinical relevance of the project, the various selected combinations of WJ460 and irradiation will be applied first to heterotopic spheroids and then PDAC organoids. Besides, to understand the mechanism behind the radiosensitization observed during treatment with WJ460, we analyzed in silico TCGA data obtained from PDAC patients that indicated a frequent and significative co-occurrence of myoferlin gene alteration with the alteration of genes implicated in DNA repair. In addition, RNA sequencing was performed. The bioinformatic analysis of the results revealed the alteration of gene sets linked to the G2/M phase arrest, considered as increasing radiosensitization. Pharmacological manipulation of myoferlin improves radiosensitivity in vitro. Further work is required to fully understand this discovery and translate these findings into clinical practice

Belgique

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).Importance of Myoferlin in MAMs and Global Impact on mitochondrial Network and Metabolism