Integrated intra‐ and intercellular signaling knowledge for multicellular omics analysis

Abstract

Molecular knowledge of biological processes is a cornerstone in omics data analysis. Applied to single-cell data, such analyses provide mechanistic insights into individual cells and their interactions. However, knowledge of intercellular communication is scarce, scattered across resources, and not linked to intracellular processes. To address this gap, we combined over 100 resources covering interactions and roles of proteins in inter-and intracellular signaling, as well as transcriptional and post-transcriptional regulation. We added protein complex information and annotations on function, localization, and role in diseases for each protein. The resource is available for human, and via homology translation for mouse and rat. The data are accessible via OmniPath's web service (https://omnipathdb.org/), a Cytoscape plug-in, and packages in R/Bioconductor and Python, providing access options for computational and experimental scientists. We created workflows with tutorials to facilitate the analysis of cell-cell interactions and affected downstream intracellular signaling processes. OmniPath provides a single access point to knowledge spanning intraand intercellular processes for data analysis, as we demonstrate in applications studying SARS-CoV-2 infection and ulcerative colitis.

Comparison of Resources and Methods to infer Cell-Cell Communication from Single-cell RNA Data

“…Moreover, interactions from Guide to Pharmacology 31 , CellPhoneDB 7 , and in particular Ramilowski 32 , were incorporated into subsequently published resources. All these resources are integrated into OmniPath's CCC resource 2 , along with additional CCC interactions from other sources (e.g. SIGNOR 33 , Adhesome 34 , SignaLink 35 , and others).…”

“…CCC commonly refers to interactions between secreted ligands and plasma membrane receptors. This picture can be broadened to include secreted enzymes, extracellular matrix proteins, transporters, and interactions that require the physical contact between cells, such as cell-cell adhesion proteins and gap junctions 2 . For simplicity, we refer to all of these events involving protein-protein interactions as CCC.…”

“…The available prior knowledge resources, largely composed of ligand-receptor, extracellular matrix, and adhesion interactions, are typically distinct but o en show partial overlap 2,20 . Some of these resources also provide additional details for the interactions such as information about protein complexes 2,7,13,21,22 , subcellular localisation 2,13 , and classification into signalling pathways and categories 13,21 (Supp. Table 1).…”

“…Table 1). CCC resources are o en manually curated and/or built from other resources, with varying proportions of expert curation and literature support 2,20 . Some databases gather and harmonize the information contained in the individual resources 2 .…”

“…CCC resources are o en manually curated and/or built from other resources, with varying proportions of expert curation and literature support 2,20 . Some databases gather and harmonize the information contained in the individual resources 2 . Despite the fact that CCC inference is constrained by the prior knowledge used, the impact of resource choice is largely unexplored, with the only exception, to our knowledge, of a descriptive comparison of 4 resources with one method 20 .…”