PubMed · 13430692
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M BURGER, K SEIDEL. 1957-03-29. Internal secretion.. https://pubmed.ncbi.nlm.nih.gov/13430692/
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MOTIVATION: Algorithms for ligand-receptor network inference have emerged as commonly used tools to estimate cell-cell communication from reference single-cell data. Many studies employ these algorithms to compare signaling between conditions and lack methods to statistically identify signals that are significantly different. We previously developed the cell communication inference algorithm Domino, which considers ligand and receptor gene expression in association with downstream transcription factor activity scoring. We developed the dominoSignal software to innovate upon Domino and extend its functionality to test statistically differential cellular signaling. RESULTS: This new functionality includes the compilation of active signals as linkages from multiple subjects in a single-cell data set and testing condition-dependent signaling linkage. The software is applicable for analysis of single-cell data sets with multiple subjects as biological replicates as well as with bootstrapped replicates from data sets with few or pooled subjects. We use simulation studies to benchmark the number of subjects in compared groups and cells within an annotated cell type sufficient to accurately identify differential linkages. We demonstrate the application of the Differential Cell Signaling Test (DCST) in the dominoSignal software to investigate consequences of cancer cell phenotypes and immunotherapy on cell-cell communication in tumor microenvironments. These applications in cancer studies demonstrate the ability of differential cell signaling analysis to infer changes to cell communication networks from therapeutic or experimental perturbations, which is broadly applicable across biological systems. AVAILABILITY: dominoSignal is available through Bioconductor at https://www.bioconductor.org/packages/release/bioc/html/dominoSignal.html.
The dermis is the main site of melanoma invasion. Matrix metalloproteinases (MMPs), especially MMP-2, produced by melanoma or surrounding stromal cells, are essential for the destruction of dermal extracellular matrix. Here, we examined how dermal fibroblasts influenced proliferation, MMP-2 secretion and invasion of human melanoma cell lines in vitro. Human melanoma cell lines M3 Da and M1Dor were cocultured with dermal fibroblasts under non-contact and contact conditions in order to assess both soluble and insoluble factors, respectively. Zymographic analysis showed that the levels of MMP-2 and TIMP-2 in melanoma cells were not altered in non-contact cocultures when compared with those in individual cultures. However, in contact cocultures, the expression of MMP-2 in membrane extracts was enhanced. Under our coculture conditions, dermal fibroblasts failed to upregulate melanoma cell invasion through a three-dimensional type I collagen matrix. Since stromal and cancer cell contacts have been shown to occur after disruption of the extracellular matrix, we hypothesized that fibroblasts may influence melanoma cell invasion after the beginning of tumor progression through the dermis.
Gap junctional intercellular communication (GJIC) is essential in the maintenance of tissue homeostasis and has been implicated in tumor suppression. Recent studies have indicated that GJIC is also involved in cellular stress responses to low dose ionizing radiation, UV light and hydrogen peroxide. However, the contribution of GJIC to the heat stress response has not yet been elucidated. We here demonstrate a potential link between GJIC and the heat stress response. First, we investigated whether the abolition of GJIC by lindane affects heat sensitivity in normal human cells. Lindane potentiated cell killing by heat shock at 43 degrees C, whereas little or no cytotoxicity was observed at 37 degrees C. Nuclear translocation of heat shock protein 72 (HSP72) was interrupted by lindane, although its induction was not affected. These results indicate that lindane exacerbates hyperthermic lethality via disrupted nuclear translocation of HSP72 protein. Second, we assessed whether heat shock alters GJIC and phosphorylation of gap junction connexin (Cx) proteins in normal human cells. Persistent heat treatment augmented Cx43 phosphorylation in a heat- and time-dependent fashion and this phosphorylation was recovered after heat shock. GJIC was also disturbed by heat shock. These results indicate that heat shock augments Cx43 phosphorylation leading to GJIC abrogation. Our present results imply that GJIC contributes to protection against heat stress and that loss of GJIC function during carcinogenesis exacerbates hyperthermic lethality.