Feasibility of Inferring Spatial Transcriptomics from Single-Cell Histological Patterns for Studying Colon Cancer Tumor Heterogeneity.

Background: Spatial transcriptomics involves studying the spatial organization of gene expression within tissues, offering insights into the molecular diversity of tumors. While spatial gene expression is commonly amalgamated from 1-10 cells across 50-micron spots, recent methods have demonstrated the capability to disaggregate this information at subspot resolution by leveraging both expression and histological patterns. However, elucidating such information from histology alone presents a significant challenge but if solved can better permit spatial molecular analysis at cellular resolution for instances where Visium data is not available, reducing study costs. This study explores integrating single-cell histological and transcriptomic data to infer spatial mRNA expression patterns in whole slide images collected from a cohort of stage pT3 colorectal cancer patients. A cell graph neural network algorithm was developed to align histological information extracted from detected cells with single cell RNA patterns through optimal transport methods, facilitating the analysis of cellular groupings and gene relationships. This approach leveraged spot-level expression as an intermediary to co-map histological and transcriptomic information at the single-cell level.

Results: Our study demonstrated that single-cell transcriptional heterogeneity within a spot could be predicted from histological markers extracted from cells detected within a spot. Furthermore, our model exhibited proficiency in delineating overarching gene expression patterns across whole-slide images. This approach compared favorably to traditional patch-based computer vision methods as well as other methods which did not incorporate single cell expression during the model fitting procedures. Topological nuances of single-cell expression within a Visium spot were preserved using the developed methodology.

Conclusion: This innovative approach augments the resolution of spatial molecular assays utilizing histology as a sole input through synergistic co-mapping of histological and transcriptomic datasets at the single-cell level, anchored by spatial transcriptomics. While initial results are promising, they warrant rigorous validation. This includes collaborating with pathologists for precise spatial identification of distinct cell types and utilizing sophisticated assays, such as Xenium, to attain deeper subcellular insights.