<div> <p>Pancreatic ductal adenocarcinoma (PDAC) is a poorly immune responsive, treatment refractory disease, representing the fourth leading cause of cancer deaths in the United States. A lack of significant improvements in patient prognoses over the last few decades highlights the necessity for a more basic understanding of how PDAC develops and progresses. To this end, the research outlined here investigates the contributions of SOX9 and PAR1 in PDAC initiation and tumor immune evasion, respectively. </p> <p>SOX9 is a developmental transcription factor important for proper pancreas development that is restricted to only a small subset of cells in the adult organ. However, SOX9 is aberrantly expressed in precancerous lesions of the pancreas and throughout PDAC development. Using genetically engineered mouse models we demonstrated that PDAC precursor lesions cannot form in the absence of SOX9 and conversely formed at an accelerated rate when SOX9 was ectopically expressed. Surprisingly deletion of SOX9 in primary mouse PDAC cell lines had no impact on tumor growth in subcutaneous allograft experiments, indicating that although SOX9 expression is necessary for PDAC initiation, it is dispensable in many cases for tumor maintenance and growth. Research investigating the transcriptional changes induced by SOX9 prior to lesion formation is ongoing to identify additional downstream factors critical for disease initiation. </p> <p>Previous research has shown that PDAC tumors frequently display low levels of immune infiltration, which is a major limitation for the use of immune-based therapeutics and is generally an unfavorable prognostic factor. We show that in primary mouse tumor cells ablation of the thrombin receptor PAR1 caused a significant increase in the infiltration of tumor targeting CD8a⁺T cells which in turn were found to eliminate PAR1 knockout tumors. When PAR1^KO and PAR1 expressing PDAC tumor cells were co-injected into wild type mice, cells lacking PAR1 were preferentially targeted and eliminated by the immune system, indicating that PAR1 provides cell autonomous protection during an active anti-tumor adaptive immune response. Furthermore, we identified a previously underappreciated association between PAR1-mediated expression of <i>Csf2</i> and <i>Ptgs2</i>, and PDAC tumor immune evasion. Together these findings provide novel insights into the mechanisms and drivers of PDAC initiation and immune evasion.</p> </div> <br>

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Networks of interneurons within the spinal cord coordinate the rhythmic activation of muscles during locomotion. These networks are subject to extensive neuromodulation, ensuring appropriate behavioural output. Astrocytes are proposed to detect neuronal activity via Gαq-linked G-protein coupled receptors and to secrete neuromodulators in response. However, there is currently a paucity of evidence that astrocytic information processing of this kind is important in behaviour. Here, it is shown that protease-activated receptor-1 (PAR1), a Gαq-linked receptor, is preferentially expressed by glia in the spinal cords of postnatal mice. During ongoing locomotor-related network activity in isolated spinal cords, PAR1 activation stimulates release of adenosine triphosphate (ATP), which is hydrolysed to adenosine extracellularly. Adenosine then activates A1 receptors to reduce the frequency of locomotor-related bursting recorded from ventral roots. This entails inhibition of D1 dopamine receptors, activation of which enhances burst frequency. The effect of A1 blockade scales with network activity, consistent with activity-dependent production of adenosine by glia. Astrocytes also regulate activity by controlling the availability of D-serine or glycine, both of which act as co-agonists of glutamate at N-methyl-D-aspartate receptors (NMDARs). The importance of NMDAR regulation for locomotor-related activity is demonstrated by blockade of NMDARs, which reduces burst frequency and amplitude. Bath-applied D-serine increases the frequency of locomotor-related bursting but not intense synchronous bursting produced by blockade of inhibitory transmission, implying activity-dependent regulation of co-agonist availability. Depletion of endogenous D-serine increases the frequency of locomotor-related but not synchronous bursting, indicating that D-serine is required at a subset of NMDARs expressed by inhibitory interneurons. Blockade of the astrocytic glycine transporter GlyT1 increases the frequency of locomotor-related activity, but application of glycine has no effect, indicating that GlyT1 regulates glycine at excitatory synapses. These results indicate that glia play an important role in regulating the output of spinal locomotor networks.