Connecting spatial regions to clinical phenotypes by transferring knowledge from bulk gene expression data

Spatially resolved transcriptomics (SRT) technology has enabled a new level of knowledge about tumors. Many critical tumor properties, such as invasiveness and growth, depend on both specific transcriptomic changes in tumor cells and the tumor microenvironment. However, computational methods to study clinical phenotypes of spatial regions, such as hazard and drug response, have not yet been developed. Since clinical phenotypes are measured at the patient level and not at the level of spatial regions, such a method would require transferring knowledge from the patient level domain to the spot level domain. To overcome this challenge, we developed SpacePhenotyper. Our approach uses algebraic spectral techniques to transfer the predictive relationship between gene expression and clinical phenotypes from bulk gene expression data to SRT data. Our approach captures a gene expression pattern that is predictive of the phenotype of interest in the form of a vector, the Eigen-Patient, which is then used to quantify the phenotype in spatial spots. After extensively validating SpacePhenotyper on simulated and real data, we utilize it to study how the spatial heterogeneity of breast cancer tumors influences residual cancer burden after treatment. By assigning relative quantities of clinical phenotypes to spatial locations, SpacePhenotyper has proven a powerful tool for the identification and interpretation of transcriptional changes over spatial regions and of spatially-regulated patterns of cellular states.