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M2OST: Many-to-one Regression for Predicting Spatial Transcriptomics from Digital Pathology Images
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Proposes M2OST, a many-to-one Transformer that jointly predicts a spot's spatial gene expression from three pyramid levels of the same WSI patch, with decoupled intra-level, cross-level token and channel mixing.
Problem
Predicting spatial transcriptomics (ST) gene expression from histopathology whole slide images; existing patch-level regression methods ignore multi-scale pyramid information and inter-spot visual context, and slide-level methods are large and costly.
Approach
Treat ST prediction as many-to-one regression: multiple magnification levels of the same spot are fed through weight-decoupled streams with deformable patch embedding, cross-level attention and cross-level channel mixing, yielding a compact Transformer with fewer parameters and FLOPs.
Key results
- M2OST reaches mean PCC of 48.07% on HBC, 44.17% on HER2+ and 50.50% on cSCC, the best among compared methods.
- M2OST uses 6.81M parameters and 2.24 GFLOPs, versus 7.21M and 2.87 GFLOPs for ST-Net, and fewer than slide-level Hist2ST (675.5M parameters).
- Masking one random level in 75% of samples drops PCC by 7.75%, 7.65% and 3.14% on the three datasets.
Measured effects reported in the paper
| What was changed | Where | Measured | Effect |
|---|---|---|---|
| Add DPE instead of ordinary patch embedding (ablation) | M2OST · HBC, HER2+, and cSCC | PCC (%): 47.13 -> 48.07; 43.10 -> 44.17; 49.35 -> 50.50 | Helped |
| Use separate ITMMs rather than unified self-attention (ablation) | M2OST · HBC, HER2+, and cSCC | PCC (%): 47.03 -> 48.07; 42.99 -> 44.17; 49.48 -> 50.50 | Helped |
| Add CTMM instead of simple concatenation for cross-level fusion (ablation) | M2OST · HBC, HER2+, and cSCC | PCC (%): 46.34 -> 48.07; 42.57 -> 44.17; 48.81 -> 50.50 | Helped |
| Use CCMM instead of ordinary fully connected layers for channel mixing (ablation) | M2OST · HBC, HER2+, and cSCC | PCC (%): 46.12 -> 48.07; 42.55 -> 44.17; 48.66 -> 50.50 | Helped |
| Add level 1 and level 2 image patches to level 0 inputs (ablation) | M2OST · HBC, HER2+, and cSCC | PCC (%): 46.92 -> 48.07; 43.12 -> 44.17; 49.31 -> 50.50 | Helped |
| Mask one random input level in more samples (ablation) | M2OST on the fused dataset · HBC, HER2+, and cSCC | PCC (%): 39.46 -> 31.71; 39.97 -> 32.32; 37.33 -> 34.19 | Hurt |
| Apply many-to-one modeling with ResNet-50 patch embeddings (ablation) | ResNet-50 · HBC, HER2+, and cSCC | PCC (%): +1.71; +1.43; +1.46 | Helped |
| Apply many-to-one modeling with ST-Net patch embeddings (ablation) | ST-Net · HBC, HER2+, and cSCC | PCC (%): +1.12; +1.72; +1.39 | Helped |
| Apply many-to-one modeling with ViT patch embeddings (ablation) | ViT · HBC, HER2+, and cSCC | PCC (%): +1.95; +0.63; +1.81 | Helped |
Surprising findings
- Using only level 0 (one-to-one) M2OST does not surpass simple baselines such as ResNet-50 and ST-Net, so gains come from the many-to-one scheme.
- Slide-level methods (HisToGene, Hist2ST) underperform patch-level methods, suggesting inter-spot correlations add little for spot-level gene prediction.
Limitations
- As a spot-level method, it predicts one spot at a time and is less efficient than slide-level methods for generating full ST maps.
- End-to-end spot-level training perceives only limited nearby non-local context in a WSI.
- Performance drops notably when image levels are missing at test time.
Experimental setup
Datasets: HBC HER2+ cSCC
Benchmarks: HBC HER2+ cSCC
Metrics: PCC RMSE parameter count FLOPs
Baselines: ResNet50 ViT-B/16 Swin-T ConvNeXt-T CrossViT DeepSpaCE ST-Net HisToGene Hist2ST BLEEP HIPT/iStar
Builds on: ViT CrossViT Random Mask Self-Attention squeeze-and-excitation
Closest papers by meaning
- STimage-1K4M: A histopathology image-gene expression dataset for spatial transcriptomics (NeurIPS 2024 · similarity 0.92)
- Diffusion Generative Modeling for Spatially Resolved Gene Expression Inference from Histology Images (ICLR 2025 · similarity 0.89)
- Multi-modal Topology-embedded Graph Learning for Spatially Resolved Genes Prediction from Pathology Images with Prior Gene Similarity Information (CVPR 2025 · similarity 0.89)
- Preserving DEG Rankings for Gene Discovery in Histology-Based Spatial Gene Expression Prediction (NeurIPS 2026 · similarity 0.89)
- Towards Scalable Context-Aware Single-Cell Spatial Transcriptomics Prediction from Histology Images (NeurIPS 2026 · similarity 0.89)
- MERGE: Multi-faceted Hierarchical Graph-based GNN for Gene Expression Prediction from Whole Slide Histopathology Images (CVPR 2025 · similarity 0.89)
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