Project description:The SecAct (Secreted Activity) model infers secreted-protein signaling activity from spatial, single-cell, and bulk transcriptomics data. Using SecAct, LY86 was identified and validated in vivo as a promising immunotherapy target.
Project description:In the social amoebae (Dictyostelia) quorum sensing system mediates aggregation of single cells into multicellular aggregates by chemotactic movement towards gradients of diffusible molecules known as acrasins. The acrasin of P. violaceum is the unusual dipeptide N-propionyl-gamma-L-glutamyl-L-ornithine-delta-lactam-ethylester, known as glorin. Phylogenetic analysis has indicated that P. violaceum is more related to the most derived group 4 dictyostelids than to the ancient group 2 polysphondylids such as P. pallidum. Nevertheless it has been reported that P. pallidum cells respond to glorin in chemotaxis assays. This has led to the assumption that glorin-based communication may be the most ancient form of intercellular communication that Dictyostelia invented to organize early steps of multicellular development. In this study we show that glorin mediates rapid changes in gene expression at the transition from vegetative growth to aggregation, apparently without pronounced cross-talk with the cyclic AMP-based communication system that coordinates post-aggregation events in this species. We describe glorin-mediated changes in gene expression in the social amoeba Polysphondylium pallidum at the transition from unicellular growth to multicellular development. Comparison of gene expression in growing cells versus cells starving for 2 or 3 hours in the presence or absence of glorin.
Project description:Inference of cell-cell communication from single-cell RNA-sequencing data is a powerful technique to uncover intercellular communication pathways, yet existing methods perform this analysis at the level of the cell type or cluster, discarding single-cell level information. Here we present Scriabin, a flexible and scalable framework for comparative analysis of cell-cell communication at single-cell resolution that is performed without cell aggregation or downsampling. We use multiple published atlas-scale datasets, genetic perturbation screens, and direct experimental validation to show that Scriabin accurately recovers expected cell-cell communication edges and identifies communication networks that can be obscured by agglomerative methods. Additionally, we use spatial transcriptomic data to show that Scriabin can uncover spatial features of interaction from dissociated data alone. Finally, we demonstrate applications to longitudinal datasets to follow communication pathways operating between timepoints. Our approach represents a broadly applicable strategy to reveal the full structure of niche-phenotype relationships in health and disease.
Project description:Ewing and osteosarcoma are bone sarcomas that occur predominantly in adolescents. In the setting of metastatic or recurrent disease, overall prognosis is poor. While immunotherapy is effective for some adult soft tissue sarcoma, limited success has been achieved with immunotherapy for pediatric bone sarcomas. To better understand antitumor immunity in Ewing and osteosarcoma patients, we performed single-cell RNAseq on peripheral blood and tumor infiltrating immune populations using 10X Genomics droplet-based approach. We also included peripheral blood from healthy adolescent blood donors as a comparator. Utilizing these transcriptional profiles, we characterized tumor infiltrating CD8+ T cells and myeloid cells and identified intercellular communication networks in both primary and recurrent disease.
Project description:In the social amoebae (Dictyostelia) quorum sensing system mediates aggregation of single cells into multicellular aggregates by chemotactic movement towards gradients of diffusible molecules known as acrasins. The acrasin of P. violaceum is the unusual dipeptide N-propionyl-gamma-L-glutamyl-L-ornithine-delta-lactam-ethylester, known as glorin. Phylogenetic analysis has indicated that P. violaceum is more related to the most derived group 4 dictyostelids than to the ancient group 2 polysphondylids such as P. pallidum. Nevertheless it has been reported that P. pallidum cells respond to glorin in chemotaxis assays. This has led to the assumption that glorin-based communication may be the most ancient form of intercellular communication that Dictyostelia invented to organize early steps of multicellular development. In this study we show that glorin mediates rapid changes in gene expression at the transition from vegetative growth to aggregation, apparently without pronounced cross-talk with the cyclic AMP-based communication system that coordinates post-aggregation events in this species. We describe glorin-mediated changes in gene expression in the social amoeba Polysphondylium pallidum at the transition from unicellular growth to multicellular development.