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| Item Type: | Preprint |
|---|---|
| Title: | Unravelling drug resistant proteotypes through phenotype-resolved proteomics of single-cell derived colonies |
| Creators: |
Qin, Di  ORCID: https://orcid.org/0000-0002-9730-4072, Das, Ridhima ORCID: https://orcid.org/0009-0007-0238-5935, Schallenberg, Simon ORCID: https://orcid.org/0000-0002-7897-7116, Riecken, Kristoffer ORCID: https://orcid.org/0000-0001-9050-6766, Tinhofer, Ingeborg ORCID: https://orcid.org/0000-0002-0512-549X and Coscia, Fabian ORCID: https://orcid.org/0000-0002-2244-5081
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| Abstract: | Drug resistance remains a major cause of treatment failure and disease progression and is closely linked to intratumoral heterogeneity. Mass spectrometry (MS)-based single-cell proteomics (SCP) can resolve drug-resistant cell states, but current methods lack clonal and phenotype information and are often confounded by cell-cycle and cell-size effects. Here, we introduce PhenoSCoP, a microscopy-guided discovery proteomics framework that profiles single-cell-derived colonies to map proteomic heterogeneity while preserving clonal origin and image-defined phenotypes. In head and neck squamous cell carcinoma models, PhenoSCoP distinguished heritable clone-intrinsic cisplatin (CP) response programs from adaptive treatment-induced changes, uncovered pre-existing resistant-like proteotypes in treatment-naive populations, and identified an NDUFB11-associated mitochondrial vulnerability in a resistant clone. In patient-derived primary HNSCC cells, CP-tolerant cells resolved into two proteomic states with distinct phenotypes and high or low S100A7/A8/A9 expression. These programs were also detected in HNSCC patient tissues and, in an illustrative matched progression case, increased across metastatic sites. PhenoSCoP therefore provides a phenotype-resolved framework for discovering stable and adaptive proteotypes associated with therapeutic response. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.10.11.681009v3 |
| Date: | 3 September 2026 |
| Additional Information: | ProteomeXchange dataset PXD069541 has been reserved by the PRIDE repository for a dataset that has been deposited, but is not yet publicly released and announced to ProteomeXchange. |
| Official Publication: | https://doi.org/10.1101/2025.10.11.681009 |
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