Spatial Transcriptomics Reveals HER2/AR-Associated Heterogeneity and Alternative Surface Targets in Salivary Duct...

Salivary duct carcinoma (SDC) is an aggressive malignancy primarily treated with human epidermal growth factor receptor 2 (HER2)- and androgen receptor (AR)-directed therapies in the recurrent or metastatic setting, although therapeutic responses remain heterogeneous. We used spatial transcriptomics to characterize intratumoral heterogeneity and to identify alternative therapeutic targets. Spatial transcriptomic profiling was performed on four formalin-fixed, paraffin-embedded SDC specimens using the 10× Genomics Visium platform. Tumor regions were characterized according to spatial HER2 and AR expression and their corresponding transcriptional signatures. Candidate cell-surface targets in HER2/AR-non-associated regions were identified using the SURFY human surfaceome and prioritized based on low expression in matched normal salivary gland tissue and therapeutic relevance. Spatial mapping revealed heterogeneous distributions of HER2- and AR-associated transcriptional states within individual tumors, including HER2/AR-non-associated regions in all four specimens. Surfaceome screening identified several candidate targets with low expression in matched normal salivary gland tissue, among which ALCAM showed consistently broad whole-tumor coverage across all four specimens. These findings highlight substantial intratumoral heterogeneity in SDC and identify alternative cell-surface targets that may complement HER2- and AR-directed therapies.