MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer

Cellular interactions in the tumor microenvironment influence neoplastic progression in pancreatic ductal adenocarcinoma. One underlying mechanism is the induction of the prognostically unfavorable epithelial-mesenchymal-transition-like tumor budding. Our aim is to explore the expression of microRNAs implicated in the regulation of tumor budding focusing on the microenvironment of the invasive front. To this end, RNA from laser-capture-microdissected material of the main tumor, tumor buds, juxta-tumoral stroma, tumor-remote stroma, and non-neoplastic pancreatic parenchyma from pancreatic cancer cases with (n=7) and without (n=6) tumor budding was analyzed by qRT-PCR for the expression of a panel of miRNAs that are known to be implicated in the regulation of epithelial-mesenchymal transition, including miR-21, miR-183, miR-200b, miR-200c, miR-203, miR-205, miR-210, and miR-217. Here we show that at the invasive front of pancreatic ductal adenocarcinoma, specific microRNAs, are differentially expressed between tumor buds and main tumor cells and between cases with and without tumor budding, indicating their involvement in the regulation of the budding phenotype. Notably, miR-200b and miR-200c were significantly downregulated in the tumor buds. Consistent with this finding, they negatively correlated with the expression of epithelial-mesenchymal-transition-associated E-cadherin repressors ZEB1 and ZEB2 in the budding cells (P<0.001). Interestingly, many microRNAs were also dysregulated in juxta-tumoral compared to tumor-remote stroma suggesting that juxta-tumoral stroma contributes to microRNA dysregulation. Notably, miR-200b and miR-200c were strongly downregulated while miR-210 and miR-21 were upregulated in the juxta-tumoral vs tumor-remote stroma in carcinomas with tumor budding. In conclusion, microRNA targeting in both tumor and stromal cells could represent a treatment option for aggressive pancreatic cancer

Quinolinate and related excitotoxins: mechanisms of neurotoxicity and disease relevance

There are many ways in which neuronal damage can be produced in the brain, including the overactivation of depolarizing receptors, exposure to high levels of pro-inflammatory proteins such as cytokines, or miscellaneous toxins, but the kynurenine pathway has emerged as a novel but potentially major factor in regulating neuronal viability or death. It is the major route for the metabolism of the essential amino acid tryptophan, which is oxidized by indoleamine-2,3-dioxygenase (IDO) to a series of compounds which can activate, block, or modulate conventional neurotransmitter receptors. Quinolinic acid is an agonist at N-methyl-d-aspartate receptors, kynurenic acid is an antagonist at these and other glutamate receptors, and other kynurenine metabolites are highly redox-active. Superimposed on the discovery of this neuromodulatory pathway have been observations that activity in the pathway is linked to neurological and psychiatric disorders, correlating with disease state (as in Huntington’s disease) or cognitive function (as following bypass surgery). Together, the data accumulated to date make a strong case for this hitherto obscure pathway being a major factor in determining cell damage, death, or recovery in health and disease

Signs of Timing in Motor Cortex During Movement Preparation and Cue Anticipation

International audienceThe capacity to accurately anticipate the timing of predictable events is essential for sensorimotor behavior. Motor cortex holds an established role in movement preparation and execution. In this chapter we review the different ways in which motor cortical activity is modulated by event timing in sensorimotor delay tasks. During movement preparation, both single neuron and population responses reflect the temporal constraints of the task. Anticipatory modulations prior to sensory cues are also observed in motor cortex when the cue timing is predictable. We propose that the motor cortical activity during cue anticipation and movement preparation is embedded in a timing network that facilitates sensorimotor processing. In this context, the pre-cue and post-cue activity may reflect a presetting mechanism, complementing processing during movement execution, while prohibiting premature responses in situations requiring delayed motor output