Decoding functional cell-cell communication events by multi-view graph learning on spatial transcriptomics.

Cell-cell communication events (CEs) are mediated by multiple ligand-receptor (LR) pairs. Usually only a particular subset of CEs directly works for a specific downstream response in a particular microenvironment. We name them as functional communication events (FCEs) of the target responses. Decoding FCE-target gene relations is: important for understanding the mechanisms of many biological processes, but has been intractable due to the mixing of multiple factors and the lack of direct observations. We developed a method HoloNet for decoding FCEs using spatial transcriptomic data by integrating LR pairs, cell-type spatial distribution and downstream gene expression into a deep learning model. We modeled CEs as a multi-view network, developed an attention-based graph learning method to train the model for generating target gene expression with the CE networks, and decoded the FCEs for specific downstream genes by interpreting trained models. We applied HoloNet on three Visium datasets of breast cancer and liver cancer. The results detangled the multiple factors of FCEs by revealing how LR signals and cell types affect specific biological processes, and specified FCE-induced effects in each single cell. We conducted simulation experiments and showed that HoloNet is more reliable on LR prioritization in comparison with existing methods. HoloNet is a powerful tool to illustrate cell-cell communication landscapes and reveal vital FCEs that shape cellular phenotypes. HoloNet is available as a Python package at https://github.com/lhc17/HoloNet.