Zihui Wang

Yuxiang Lin, Ling Luo, Ying Chen et al.

Spatial transcriptomics (ST) provides high-resolution pathological images and whole-transcriptomic expression profiles at individual spots across whole-slide scales. This setting makes it an ideal data source to develop multimodal foundation models. Although recent studies attempted to fine-tune visual encoders with trainable gene encoders based on spot-level, the absence of a wider slide perspective and spatial intrinsic relationships limits their ability to capture ST-specific insights effectively. Here, we introduce ST-Align, the first foundation model designed for ST that deeply aligns image-gene pairs by incorporating spatial context, effectively bridging pathological imaging with genomic features. We design a novel pretraining framework with a three-target alignment strategy for ST-Align, enabling (1) multi-scale alignment across image-gene pairs, capturing both spot- and niche-level contexts for a comprehensive perspective, and (2) cross-level alignment of multimodal insights, connecting localized cellular characteristics and broader tissue architecture. Additionally, ST-Align employs specialized encoders tailored to distinct ST contexts, followed by an Attention-Based Fusion Network (ABFN) for enhanced multimodal fusion, effectively merging domain-shared knowledge with ST-specific insights from both pathological and genomic data. We pre-trained ST-Align on 1.3 million spot-niche pairs and evaluated its performance through two downstream tasks across six datasets, demonstrating superior zero-shot and few-shot capabilities. ST-Align highlights the potential for reducing the cost of ST and providing valuable insights into the distinction of critical compositions within human tissue.

Zheng Wang, Zihui Wang, Zheng Wang et al.

Federated learning (FL) is emerging as a promising technique for collaborative learning without local data leaving their devices. However, clients' data originating from diverse domains may degrade model performance due to domain shifts, preventing the model from learning consistent representation space. In this paper, we propose a novel FL framework, Federated Domain Shift Eraser (FDSE), to improve model performance by differently erasing each client's domain skew and enhancing their consensus. First, we formulate the model forward passing as an iterative deskewing process that extracts and then deskews features alternatively. This is efficiently achieved by decomposing each original layer in the neural network into a Domain-agnostic Feature Extractor (DFE) and a Domain-specific Skew Eraser (DSE). Then, a regularization term is applied to promise the effectiveness of feature deskewing by pulling local statistics of DSE's outputs close to the globally consistent ones. Finally, DFE modules are fairly aggregated and broadcast to all the clients to maximize their consensus, and DSE modules are personalized for each client via similarity-aware aggregation to erase their domain skew differently. Comprehensive experiments were conducted on three datasets to confirm the advantages of our method in terms of accuracy, efficiency, and generalizability.

Chen Zhang, Yilu An, Ying Chen et al.

Spatial Transcriptomics (ST) merges the benefits of pathology images and gene expression, linking molecular profiles with tissue structure to analyze spot-level function comprehensively. Predicting gene expression from histology images is a cost-effective alternative to expensive ST technologies. However, existing methods mainly focus on spot-level image-to-gene matching but fail to leverage the full hierarchical structure of ST data, especially on the gene expression side, leading to incomplete image-gene alignment. Moreover, a challenge arises from the inherent information asymmetry: gene expression profiles contain more molecular details that may lack salient visual correlates in histological images, demanding a sophisticated representation learning approach to bridge this modality gap. We propose HyperST, a framework for ST prediction that learns multi-level image-gene representations by modeling the data's inherent hierarchy within hyperbolic space, a natural geometric setting for such structures. First, we design a Multi-Level Representation Extractors to capture both spot-level and niche-level representations from each modality, providing context-aware information beyond individual spot-level image-gene pairs. Second, a Hierarchical Hyperbolic Alignment module is introduced to unify these representations, performing spatial alignment while hierarchically structuring image and gene embeddings. This alignment strategy enriches the image representations with molecular semantics, significantly improving cross-modal prediction. HyperST achieves state-of-the-art performance on four public datasets from different tissues, paving the way for more scalable and accurate spatial transcriptomics prediction.