JASPR: Joint Spatial Representation learning of histology and spatial genomics for improved virtual genomic screening and clinical prognostication

Comprehensive molecular profiling is essential for modern precision oncology but remains hindered by prohibitive costs, specimen exhaustion, and protracted turnaround times. While pathology foundation models (PFMs) have demonstrated potential for inferring molecular phenotypes from routine hematoxylin and eosin (H&E) whole-slide images (WSIs), current architectures primarily rely on vision-centric self-supervised learning or vision-language alignment, lacking the spatially resolved molecular supervision required to connect subtle morphological features with underlying genomic alterations. Spatial transcriptomics (ST) emerges as a transformative technology that enables transcriptomic quantification within intact tissue sections, thereby preserving the precise spatial link between histology and molecular profiles. In this study, we present a Spatial Transcriptomics-guided Alignment framework for Molecular Profiling (STAMP), which endows PFMs with intrinsic molecular awareness. To support this paradigm, we curated HumanST-1k, a human ST dataset spanning diverse anatomical organs and sequencing platforms. This atlas yields 1.8 million pairs of H&E patches and corresponding transcriptomic profiles, providing a corpus that links histological structures with their molecular states. To mitigate the technical noise inherent to raw transcriptomics, STAMP applies a pathway-informed alignment strategy that aggregates transcriptomic data into biologically functional pathways, which are subsequently integrated into PFMs via parameter-efficient fine-tuning. This alignment enriches the representation space of PFMs and unlocks their capacity to resolve sub-visual molecular signatures. The clinical utility of these augmented representations was validated through a multi-tier evaluation framework.

Spatial transcriptomics (ST) enables spatially resolved gene profiling but remains expensive and low-throughput, limiting large-cohort studies and routine clinical use. Predicting spatial gene expression from routine hematoxylin and eosin (H&E) slides is a promising alternative, yet under realistic leave-one-slide-out evaluation, existing models often suffer from slide-level appearance shifts and regression-driven over-smoothing that suppress biologically meaningful variation. CHRep is a two-phase framework for robust histology-to-expression prediction. In the training phase, CHRep learns a structure-aware representation by jointly optimizing correlation-aware regression, symmetric image-expression alignment, and coordinate-induced spatial topology regularization. In the inference phase, cross-slide robustness is improved without backbone fine-tuning through a lightweight calibration module trained on the training slides, which combines a non-parametric estimate from a training gallery with a magnitude-regularized correction module. Unlike prior embedding-alignment or retrieval-based transfer methods that rely on a single prediction route, CHRep couples topology-preserving representation learning with post-hoc calibration, enabling stable neighborhood retrieval and controlled bias correction under slide-level shifts. Across the three cohorts, CHRep consistently improves gene-wise correlation under leave-one-slide-out evaluation, with the largest gains observed on Alex+10x. Relative to HAGE, the Pearson correlation coefficient on all considered genes [PCC(ACG)] increases by 4.0% on cSCC and 9.8% on HER2+. Relative to mclSTExp, PCC(ACG) further improves by 39.5% on Alex+10x, together with 9.7% and 9.0% reductions in mean squared error (MSE) and mean absolute error (MAE), respectively.

Predicting spatial gene expression from routine hematoxylin and eosin (H&E) images provides a practical complement to experimental spatial transcriptomics. Existing approaches focus on local or multi-scale visual features and often treat pretrained gene representations as fixed priors, although the interpretation of local morphology and the relevance of gene priors depend on tissue context. We propose HistoGPA, a context-conditioned gene-prior attention framework that uses a shared slide-level representation in two parallel pathways: one modulates local morphological features, whereas the other conditions pretrained gene embeddings and retrieves gene-prior information through cross-attention. This design enables each spatial location to retrieve context-adapted gene-prior information using its local morphology, position, and slide context. Across ten cancer types in HEST-1k, HistoGPA achieves the highest macro-averaged gene-wise Pearson correlation coefficient among the compared methods under the same evaluation protocol for both the top-50 and top-1,500 highly variable gene sets. Additional analyses show that HistoGPA better recovers the spatial expression patterns of cancer-associated genes and yields greater agreement between clusters derived independently from predicted and ground-truth expression profiles. Together, these findings motivate a context-dependent view of histology-to-expression prediction, in which local morphological representations and gene priors are jointly adapted to the broader tissue context.