Detection of Somatic Point Mutations Directly from Spatial Transcriptomics Enables in vivo Spatiotemporal Lineage Tracing

Yang, Z.; Yao, M.; Yang, Q.; Du, Y.; Lu, J.; Wu, X.; Lin, J.; Qian, Z.; Hu, S.; Xia, Y.; Liu, H.; Zhou, Q.; Ma, X.; Luo, Y.; Fan, W.; Pei, W.; Yu, X.; Luan, J.; Zhang, Q.; Zhang, Y.; Wang, Q.; Zeng, J.; Wu, W.; Dou, Y.

doi:10.64898/2026.02.04.703493

bioRxiv · 10.64898/2026.02.04.703493

Detection of Somatic Point Mutations Directly from Spatial Transcriptomics Enables in vivo Spatiotemporal Lineage Tracing

Yang, Z.·Yao, M.·Yang, Q.·Du, Y.·Lu, J.·Wu, X.·Lin, J.·Qian, Z.·Hu, S.·Xia, Y.·Liu, H.·Zhou, Q.·Ma, X.·Luo, Y.·Fan, W.·Pei, W.·Yu, X.·Luan, J.·Zhang, Q.·Zhang, Y.·Wang, Q.·Zeng, J.·Wu, W.·Dou, Y.

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Abstract

Spatial transcriptomics reveals tissue organization but lacks in vivo lineage-tracing methods applicable to humans. We introduce SpaceTracer, a computational framework that accurately detects somatic single-nucleotide variants (SNVs) directly from spatial transcriptomics data. By leveraging naturally occurring somatic SNVs, SpaceTracer reconstructs cellular phylogenies within native tissue architecture, enabling the mapping of lineage spread, migration, lineage-coupled expression changes and lineage-aware local interactions. Applied to human cutaneous squamous cell carcinoma, it traced tumor initiation and progressions, uncovered widespread pre-invasive migration of dedifferentiated epithelial cells and characterized mutant B cells migrating from tertiary lymphoid structures (TLS) into the tumor boundary. The framework also reconstructed developmental lineages across multiple tissues and identified tissue-resident mutant immune cells. SpaceTracer thus provides a perturbation-free platform for high-resolution spatiotemporal lineage tracing, offering a transformative tool for elucidating complex biological systems--especially tumor-immune ecosystems--with direct implications for advancing cancer immunotherapy.

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Yang, Z., Yao, M., Yang, Q., Du, Y., Lu, J., Wu, X., Lin, J., Qian, Z., Hu, S., Xia, Y., Liu, H., Zhou, Q., Ma, X., Luo, Y., Fan, W., Pei, W., Yu, X., Luan, J., Zhang, Q., Zhang, Y., Wang, Q., Zeng, J., Wu, W., Dou, Y.. 2026-02-06. Detection of Somatic Point Mutations Directly from Spatial Transcriptomics Enables in vivo Spatiotemporal Lineage Tracing. https://doi.org/10.64898/2026.02.04.703493

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