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| Item Type: | Preprint |
|---|---|
| Title: | Balancing spatial resolution and proteome depth in LC-MS based spatial proteomics |
| Creators: |
Meijer, Mandy  ORCID: https://orcid.org/0000-0003-3314-1224, Hong, Jeongwoo, Pohl, Tobias ORCID: https://orcid.org/0000-0001-8698-8475, Koudelka, Tomas ORCID: https://orcid.org/0009-0008-2895-6051, Bassot, Claudio ORCID: https://orcid.org/0000-0001-7161-9028, Hörnberg, Hanna ORCID: https://orcid.org/0000-0001-9142-1932, Lee, Sumin, Rho, Hee Sool, Lee, Amos Chungwon, Pelechano, Vicent and Piazza, Ilaria ORCID: https://orcid.org/0000-0001-5895-6134
|
| Abstract: | Spatial proteomics aims to resolve protein composition within intact tissues, yet extraction-based liquid chromatography-mass spectrometry (LC-MS) workflows face an inherent trade-off: smaller sampling units increase spatial specificity, whereas larger sampling units provide greater proteome depth and robustness. As analytical sensitivity improves, sampling-unit size therefore becomes a key experimental design parameter. Current extraction-based LC-MS workflows typically rely on laser capture microdissection (LCM), where sample recovery and scalability can become limiting at low input. Spatially resolved laser-activated cell sorting (SLACS) offers an alternative tissue-isolation strategy based on single-pulse near-infrared laser activation. Here, we use SLACS to systematically examine the resolution-sensitivity trade-off across sampling units ranging from single-cell-equivalent to larger low-input tissue regions. Few-cell sampling retained substantial proteomic information relative to larger regions while increasing spatial specificity. Applied to the mouse somatosensory cortex, SLACS generated deep, layer-resolved proteomic profiles from regions corresponding to approximately 60 cells and preserved major layer-specific molecular patterns at inputs as low as approximately 6 cells. These results highlight sampling-unit size as an important experimental design parameter in extraction-based spatial proteomics and support few-cell sampling as a practical compromise between spatial specificity, proteome depth and robustness. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.08.27.747491 |
| Date: | 28 August 2026 |
| Official Publication: | https://doi.org/10.64898/2026.08.27.747491 |
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