Relationship between Stemness, Reactive Oxygen Species, and Epithelial-to-Mesenchymal Transition in Model Circulating Tumor Cells.

Most cancer deaths are caused by secondary metastasized tumors. The cells that spread these tumors are known as circulating tumor cells (CTCs). They exist in a dynamic environment, including exposure to fluid shear stress (FSS) that makes them susceptible to reactive oxygen species (ROS) generation. There are questions about the similarities of CTCs to cancer stem cells (CSCs) and whether the stem cell-like characteristics of CTCs allow them to proliferate and spread despite the biophysical obstacles during the metastatic process. One of those qualities is the ability to undergo the epithelial-to-mesenchymal transition (EMT). Here, MDA-MB-231 and MCF7 were modeled as CTCs by prolonged exposure to FSS using a spinner flask. They were tested for ROS generation, CSC, EMT, and Hippo pathway gene and protein markers using qRT-PCR and flow cytometry. MDA-MB-231 did not show significant changes in CSC markers, but did show significant changes in ROS, EMT, and Hippo markers (p < 0.05). Similarly, MCF7 showed significant changes in ROS and EMT markers (p < 0.05). Furthermore, both cell lines demonstrated the reverse mesenchymal-to-epithelial transition signature when allowed to recover after FSS. These results suggest that the degree of their stemness or aggressiveness affects their responses to externally applied biophysical forces and demonstrates a potential link between mechanotransduction, the Hippo pathway, and the induction of EMT in breast cancer cells.

Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome.

Neurodevelopmental disorders, including autism spectrum disorder, have complex polygenic etiologies. Single-gene mutations in patients can help define genetic factors and molecular mechanisms underlying neurodevelopmental disorders. Here we describe individuals with monogenic heterozygous microdeletions in ANKS1B, a predicted risk gene for autism and neuropsychiatric diseases. Affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, attention-deficit hyperactivity disorder, and speech and motor deficits. Neurons generated from patient-derived induced pluripotent stem cells demonstrate loss of the ANKS1B-encoded protein AIDA-1, a brain-specific protein highly enriched at neuronal synapses. A transgenic mouse model of Anks1b haploinsufficiency recapitulates a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction. Identification of the AIDA-1 interactome using quantitative proteomics reveals protein networks involved in synaptic function and the etiology of neurodevelopmental disorders. Our findings formalize a link between the synaptic protein AIDA-1 and a rare, previously undefined genetic disease we term ANKS1B haploinsufficiency syndrome.

Neurophysiological indices of atypical auditory processing and multisensory integration are associated with symptom severity in autism.

Atypical processing and integration of sensory inputs are hypothesized to play a role in unusual sensory reactions and social-cognitive deficits in autism spectrum disorder (ASD). Reports on the relationship between objective metrics of sensory processing and clinical symptoms, however, are surprisingly sparse. Here we examined the relationship between neurophysiological assays of sensory processing and (1) autism severity and (2) sensory sensitivities, in individuals with ASD aged 6-17. Multiple linear regression indicated significant associations between neural markers of auditory processing and multisensory integration, and autism severity. No such relationships were apparent for clinical measures of visual/auditory sensitivities. These data support that aberrant early sensory processing contributes to autism symptoms, and reveal the potential of electrophysiology to objectively subtype autism.

Developmental change in neutral processing of words by children with autism.

This study examined the development of neural processing of auditorally presented words in high functioning children with autism. The purpose was to test the hypothesis that electrophysiological abnormalities associated with impairments in early cortical processing and in semantic processing persist into early adolescence in autistic individuals. Eighteen children with autism and 18 normally developing children participated in the study. Ten of the children in each group were 8-9 years old, and 8 in each group were 11-12 years old (n = 36). Lists of words were presented auditorally; half were words belonging to a specified semantic category and half were words outside the category. Results revealed that while early cortical processing abnormalities appeared to resolve with development, children with autism in both age groups failed to exhibit differential semantic processing of in-versus out-of-category words. Further, while 8 year-olds with autism generated a large N4 (a late cognitive ERP component, which is sensitive to semantic deviance from a context) to words in both stimulus classes the 11 year-olds showed attenuated N4 relative to normal controls in response to both stimulus types. An attempt is made to integrate findings with current cognitive theories toward a parsimonious explanation of semantic classification deficits in autism.