MoSPR: Histology-to-Gene Expression Prediction with Morpho-Spatial Macrostates and Low-Rank Molecular Programs

Dongmyung Shin, Geongyu Lee, Yesung Cho, Park Jong Bae

Predicting molecular profiles from histopathology remains challenging because whole-slide images contain spatially organized, heterogeneous tissue patterns, while gene expression comprises thousands of correlated targets. We introduce MoSPR (Morpho-Spatial Program Regression), a linear framework that couples an adjacency-informed histology representation with a low-rank molecular basis. MoSPR clusters frozen patch embeddings into morphology microstates, aggregates their spatial adjacencies across the training cohort, and groups microstates with similar adjacency patterns into shared macrostates. Each slide is then represented by global morphology and macrostate-specific deviations, which are linearly mapped to coefficients of a training-derived low-rank gene-expression basis. Across three cancer cohorts from The Cancer Genome Atlas, MoSPR achieves the highest mean gene-expression prediction scores among all evaluated methods. Without pathway-level supervision, pathway scores derived from its predicted expression profiles rank first in eight of nine comparisons across three pathway collections. Ablation studies on the breast cancer cohort show complementary gains from…