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| Item Type: | Preprint |
|---|---|
| Title: | Unravelling drug resistant proteotypes through phenotype-resolved proteomics of single-cell derived colonies |
| Creators Name: | Qin, Di, Das, Ridhima, Schallenberg, Simon, Riecken, Kristoffer, Tinhofer, Ingeborg and Coscia, Fabian |
| Abstract: | Drug resistance in cancer therapy continues to significantly contribute to treatment failure and disease progression, and is linked to intratumoral heterogeneity. Mass spectrometry (MS)-based single-cell proteomics (SCP) provides a unique opportunity to uncover the mechanisms underlying drug-resistant phenotypes; however, current methods lack clonal resolution and are often confounded by cell cycle and cell size differences. Here, we introduce PhenoSCoP, a microscopy-guided discovery proteomics concept for mapping clonal proteomic heterogeneity. By distinguishing between transient and long-lived protein level changes, our approach uncovered hereditary and clone-specific programs associated with chemotherapeutic responses in head and neck squamous cell carcinoma (HNSCC) cells. Combined with fluorescence barcoding and drug treatment assays, we identified pre-existing proteotypes that strongly dominated drug-resistant cell populations. These programs also emerged in HNSCC patient samples and in relapsed tumors after chemoradiotherapy, linking drug-resistant proteotypes to intra- and inter-tissue spatial heterogeneity. In summary, we describe a robust, versatile and phenotype-resolved approach for uncovering single-cell-derived proteotypes associated with the therapeutic responses of distinct tumor cell clones. |
| Keywords: | Proteomics, Drug Resistance, Microscopy, Tumor Heterogeneity |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.10.11.681009v2 |
| Date: | 14 October 2025 |
| Official Publication: | https://doi.org/10.1101/2025.10.11.681009 |
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