Study of the mechanism of action of MMP11 in breast cancer

Notre équipe a identifié la métalloprotéase matricielle 11 (MMP11) comme étant une protéase qui participe à la progression tumorale par son activité protéolytique. Mes travaux de thèse ont permis d’apporter des éléments de compréhension sur le mécanisme d’action de la MMP11 dans la progression tumorale du cancer du sein par des approches in vitro et in vivo. Une étude d’interaction fonctionnelle a révélé que la MMP11 semble avoir une action protéolytique sur la MMP2, une autre MMP fonctionnellement associée aux phénomènes invasifs rencontrés lors de la progression tumorale. L’étude fonctionnelle de la MMP11 dans le cancer sur différents modèles précliniques de cancérogenèse mammaire a montré que la MMP11 favorise la croissance tumorale en intervenant dans plusieurs voies de signalisation impliquées dans la reprogrammation métabolique des cellules cancéreuses, leur donnant ainsi un avantage de survie et des propriétés prolifératives. Plus précisément, la MMP11 sécrétée par les adipocytes de la glande mammaire favoriserait la croissance tumorale en remodelant le microenvironnement tumoral. A long terme, la compréhension détaillée du mécanisme d’action moléculaire de la MMP11 permettra la mise au point d’une thérapie ciblée contre la MMP11.Our team had identified matrix metalloproteinase 11 (MMP11) as a protease participating to tumor progression by using its proteolytic activity. My thesis work has provided insights into the mechanism of action of MMP11 in breast cancer tumor progression through in vitro and in vivo approaches. A functional interaction study revealed that MMP11 has a potential proteolytic action on MMP2, another MMP functionally associated with invasive phenomena encountered during tumor progression. The functional study of MMP11 in different preclinical models of breast carcinogenesis has shown that MMP11 promotes tumor growth by acting on several signaling pathways involved in the metabolic reprogramming of cancer cells, thus sustaining survival and proliferation. Specifically, MMP11 secreted by mammary gland adipocytes could promote tumor growth by remodeling the tumor microenvironment. In the long term, a detailed understanding of the molecular mechanism of action of MMP11 will allow the development of a targeted therapy against MMP11

Matrix Metalloproteinase-11 Promotes Early Mouse Mammary Gland Tumor Growth through Metabolic Reprogramming and Increased IGF1/AKT/FoxO1 Signaling Pathway, Enhanced ER Stress and Alteration in Mitochondrial UPR

International audienceMatrix metalloproteinase 11 (MMP11) is an extracellular proteolytic enzyme belonging to the matrix metalloproteinase (MMP11) family. These proteases are involved in extracellular matrix (ECM) remodeling and activation of latent factors. MMP11 is a negative regulator of adipose tissue development and controls energy metabolism in vivo. In cancer, MMP11 expression is associated with poorer survival, and preclinical studies in mice showed that MMP11 accelerates tumor growth. How the metabolic role of MMP11 contributes to cancer development is poorly understood. To address this issue, we developed a series of preclinical mouse mammary gland tumor models by genetic engineering. Tumor growth was studied in mice either deficient (Los

Interleukin-32 Contributes to Human Nonalcoholic Fatty Liver Disease and Insulin Resistance

PMC6719754Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder due to increased accumulation of fat in the liver and in many cases to enhanced inflammation. Although the contribution of inflammation in the pathogenesis of NAFLD is well established, the cytokines that are involved and how they influence liver transformation are still poorly characterized. In addition, with other modifiers, inflammation influences NAFLD progression to liver cirrhosis and hepatocellular carcinoma, demonstrating the need to find new molecular targets with potential future therapeutic applications. We investigated gene signatures in 38 liver biopsies from patients with NAFLD and obesity who had received bariatric surgery and compared these to 10 control patients who had received a cholecystectomy, using DNA microarray technology. A subset of differentially expressed genes was then validated on a larger cohort of 103 patients who had received bariatric surgery for obesity; data were thoroughly analyzed in terms of correlations with NAFLD pathophysiological parameters. Finally, the impact of a specific cytokine, interleukin-32 (IL32), was addressed on primary human hepatocytes (PHHs). Transcript analysis revealed an up-regulation of proinflammatory cytokines IL32, chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL10 and of ubiquitin D (UBD), whereas down-regulation of insulin-like growth factor-binding protein 2 (IGFBP2) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) was reported in patients with NAFLD. Moreover, IL32, which is the major deregulated gene, correlated with body mass index (BMI), waist circumference, NAFLD activity score (NAS), aminotransferases (alanine aminotransferase [ALAT] and aspartate aminotransferase [ASAT]), and homeostasis model assessment of insulin resistance (HOMA-IR) index in patients. Consistent with an instrumental role in the pathophysiology of NAFLD, treatment of control human hepatocytes with recombinant IL32 leads to insulin resistance, a hallmark metabolic deregulation in NAFLD hepatocytes. Conclusion: IL32 has a critical role in the pathogenesis of NAFLD and could be considered as a therapeutic target in patients

Forelimb Treatment in a Large Cohort of Dystrophic Dogs Supports Delivery of a Recombinant AAV for Exon Skipping in Duchenne Patients

International audienceDuchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by mutations in the dystrophin gene, without curative treatment yet available. Our study provides, for the first time, the overall safety profile and therapeutic dose of a recombinant adeno-associated virus vector, serotype 8 (rAAV8) carrying a modified U7snRNA sequence promoting exon skipping to restore a functional in-frame dystrophin transcript, and injected by locoregional transvenous perfusion of the forelimb. Eighteen Golden Retriever Muscular Dystrophy (GRMD) dogs were exposed to increasing doses of GMP-manufactured vector. Treatment was well tolerated in all, and no acute nor delayed adverse effect, including systemic and immune toxicity was detected. There was a dose relationship for the amount of exon skipping with up to 80% of myofibers expressing dystrophin at the highest dose. Similarly, histological, nuclear magnetic resonance pathological indices and strength improvement responded in a dose-dependent manner. The systematic comparison of effects using different independent methods, allowed to define a minimum threshold of dystrophin expressing fibers (>33% for structural measures and >40% for strength) under which there was no clear-cut therapeutic effect. Altogether, these results support the concept of a phase 1/2 trial of locoregional delivery into upper limbs of nonambulatory DMD patients