Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling contributes to tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased PaCSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients

Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is an extremely lethal disease due to late diagnosis, aggressiveness and lack of effective therapies. Considering its intrinsic heterogeneity, patient stratification models based on transcriptomic and genomic signatures, with partially overlapping subgroups, have been established. Besides molecular alterations, PDAC tumours show a strong desmoplastic response, resulting in profound metabolic reprogramming involving increased glucose and amino acid consumption, as well as lipid scavenging and biosynthesis. Interestingly, recent works have also revealed the existence of metabolic subtypes with differential prognosis within PDAC, which correlated to defined molecular subclasses in patients: lipogenic subtype correlated with a classical/progenitor signature, while glycolytic tumours associated with the highly aggressive basal/squamous profile. Bioinformatic analyses have demonstrated that the representative genes of each metabolic subtype are up-regulated in PDAC samples and predict patient survival. This suggests a relationship between the genetic signature, metabolic profile, and aggressiveness of the tumour. Considering all this, defining metabolic subtypes represents a clear opportunity for patient stratification considering tumour functional behaviour independently of their mutational background

The impact of high-salt diet on Type I Diabetes

Today, autoimmune diseases are a serious problem for humanity and constitute severe, sometimes debilitating health complications. Approximately 6% of the population has an autoimmune disease and the incidence is increasing worldwide. One of the reasons for their development is the improper regulation of the immune system, in which regulatory T cells (Tregs) play an important role. Genetic and environment factors have a major impact on the initiation and progression of these diseases. Developed countries create a milieu in which cardiovascular, metabolic, and autoimmune diseases flourish. In particular, Western diet, including high-fat, high-sugar, high-protein, and high-salt consumption, along with regular consumption of processed and ‘fast foods’, encourages the development of obesity, metabolic syndrome, and cardiovascular morbidity and mortality. In some recent studies, high-salt diet has also been reported to influence the symptoms of autoimmune diseases and decrease Treg functionality. Therefore, the aim of the current project was to study whether a high-salt diet could trigger the development of autoimmune diseases in the non-obese diabetic (NOD) mouse model, focusing in this dissertation on the development of type 1 diabetes.Here, we found that a high-salt diet did not elicit type 1 diabetes development in 16-week-old NOD mice with ongoing islet inflammation. These results were unexpected as mice fed with a similar high-salt regimen developed a more severe type of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Moreover, high-salt intake aggravated the symptoms of systemic lupus erythematosus, collagen-induced arthritis and experimental colitis. We assume however that the composition of the HSD and especially the origin of its proteins being 24% casein might have impeded the observations. When maintained on a standard chow, which normally contains natural non-purified ingredients, like wheat middlings, wheat germ, and soybeans, NOD mice have the greatest diabetes incidence. In contrast, the introduction of semi-purified casein- or hydrolyzed casein-based diets are the least diabetogenic when mice are maintained on these diets from a very young age. Although our mice were kept until 16 week of age on a natural ingredient diet, the switch to a diet with casein as the major protein source might have prevented the further development of type 1 diabetes.<br /

Metabolic determinants of stemness in medulloblastoma

Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glut athione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB