The Role of Axon Guidance Signaling in the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is a devastating disease, with the lowest stage-combined 5-year survival rate of any cancer type at 9%. One major attribute for this poor prognosis is the lack of effective treatments in preventing and controlling metastasis. Majority of patients present with advanced or metastatic disease upon diagnosis, and only about 20% of patients are eligible surgical resection, which is the only curative therapy for PDA. Drug targeting common disease mutations has proved difficult and further understanding of PDA biology is necessary for the development of new treatments. While genetic mutations in neoplastic cells stimulate disease generation, PDA cells only account for 10-30% of the total tumor volume, and the remaining tumor volume is comprised of several other cell types that significantly aid tumorigenesis and metastatic spread. Of all the components in the tumor microenvironment, the biology behind the neuronal-tumor signaling is the least understood; yet, several studies have highlighted the unique importance of PDA-neural cell signaling in PDA disease development. Tumor cells often invade surrounding nerves, in PDA, termed perineural invasion, and this histological disease characteristic is associated with worsened overall prognosis. Moreover, increased nerve innervation and neural hypertrophy in the tumor microenvironment is common in PDA, yet its role is poorly understood. This research describes the role of axon guidance molecules, particularly Sema3D and PlexinD1 in the development and metastasis of PDA. We have found Sema3D and PlexinD1 to be significantly associated with increased tumor cell invasion, perineural invasion, disease progression and tumor cell metastasis in PDA. The mechanism of Sema3D on PDA cells is also explored. This research provides new in vitro and in vivo evidence of the role of Sema3D and PlexinD1 signaling in the progression of PDA, which was previously unknown. This enhanced understanding of PDA-neuronal cell biology in the tumor microenvironment can be translated to provide targeted clinical benefit for PDA patients

Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution

BackgroundAsthma is a complex disorder influenced by genetics and the environment. Recent findings have linked abnormal DNA methylation in T cells with asthma; however, the potential dysregulation of methylation in airway epithelial cells is unknown. Studies of mouse models of asthma have observed greater levels of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation 1 (TET1) expression in lungs. TET proteins are known to catalyze methylation through modification of 5-methylcytosine to 5-hmC.ObjectiveWe sought to examine the association of TET1 methylation with asthma and traffic-related air pollution (TRAP).MethodsTET1 methylation levels from DNA derived from nasal airway epithelial cells collected from 12 African American children with physician-diagnosed asthma and their nonasthmatic siblings were measured by using Illumina 450K arrays. Regions of interest were verified by means of locus-specific pyrosequencing in 35 sibling pairs and replicated in an independent population (n = 186). Exposure to TRAP in participants' early life and at current home addresses was estimated by using a land-use regression model. Methylation studies in saliva, PBMCs, and human bronchial epithelial cells were done to support our findings.ResultsLoss of methylation at a single CpG site in the TET1 promoter (cg23602092) and increased global 5-hmC levels were significantly associated with asthma. In contrast, TRAP exposure at participants' current homes significantly increased methylation at the same site. Patterns were consistent across tissue sample types. 5-Aza-2'-deoxycytidine and diesel exhaust particle exposure in human bronchial epithelial cells was associated with altered TET1 methylation and expression and global 5-hmC levels.ConclusionsOur findings suggest a possible role of TET1 methylation in asthmatic patients and response to TRAP

Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution

BackgroundAsthma is a complex disorder influenced by genetics and the environment. Recent findings have linked abnormal DNA methylation in T cells with asthma; however, the potential dysregulation of methylation in airway epithelial cells is unknown. Studies of mouse models of asthma have observed greater levels of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation 1 (TET1) expression in lungs. TET proteins are known to catalyze methylation through modification of 5-methylcytosine to 5-hmC.ObjectiveWe sought to examine the association of TET1 methylation with asthma and traffic-related air pollution (TRAP).MethodsTET1 methylation levels from DNA derived from nasal airway epithelial cells collected from 12 African American children with physician-diagnosed asthma and their nonasthmatic siblings were measured by using Illumina 450K arrays. Regions of interest were verified by means of locus-specific pyrosequencing in 35 sibling pairs and replicated in an independent population (n = 186). Exposure to TRAP in participants' early life and at current home addresses was estimated by using a land-use regression model. Methylation studies in saliva, PBMCs, and human bronchial epithelial cells were done to support our findings.ResultsLoss of methylation at a single CpG site in the TET1 promoter (cg23602092) and increased global 5-hmC levels were significantly associated with asthma. In contrast, TRAP exposure at participants' current homes significantly increased methylation at the same site. Patterns were consistent across tissue sample types. 5-Aza-2'-deoxycytidine and diesel exhaust particle exposure in human bronchial epithelial cells was associated with altered TET1 methylation and expression and global 5-hmC levels.ConclusionsOur findings suggest a possible role of TET1 methylation in asthmatic patients and response to TRAP