TopSpace: spatial topic modeling for unsupervised discovery of multicellular spatial tissue structures in multiplex...

Understanding the spatial architecture of tissues is essential for decoding the complex interactions within cellular ecosystems and their implications for disease pathology and clinical outcomes. Recent advances in multiplex imaging technologies have enabled high-resolution profiling of cellular phenotypes and their spatial distributions, revealing critical roles of tissue structures such as tertiary lymphoid structures (TLSs) in shaping immune responses and influencing disease progression. However, existing methods for analyzing spatial tissue structures often rely on hard clustering or adjacency-based spatial models, which are limited in capturing the nuanced and overlapping nature of cellular communities. To address these challenges, we develop a novel spatial topic modeling framework for the unsupervised discovery of spatial tissue structures in multiplex imaging data.

We propose TopSpace, a novel Bayesian spatial topic model that integrates Gaussian processes into latent Dirichlet allocation to flexibly model spatial dependencies in tissue microenvironments. By leveraging the Bayesian framework, TopSpace supports multicellular mixed-membership clustering and offers key inferential advantages, including robust uncertainty quantification and data-driven determination of the number of multicellular microenvironments. We demonstrate the utility of TopSpace through simulations and a case study on non-small cell lung cancer (NSCLC) data. Simulations show that TopSpace accurately recovers latent tissue microenvironments and spatial clustering patterns, outperforming existing methods in scenarios with varying spatial dependencies. Applied to NSCLC data, TopSpace successfully identifies TLS and captures their spatial probability distribution, which strongly correlates with patient survival outcomes.