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LY6D marks pre-existing resistant basosquamous tumor subpopulations
Improved response to canonical therapies requires a mechanistic understanding of dynamic tumor heterogeneity by identifying discrete cellular populations with enhanced cellular plasticity. We have previously demonstrated distinct resistance mechanisms in skin basal cell carcinomas, but a comprehensi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9726704/ https://www.ncbi.nlm.nih.gov/pubmed/36473848 http://dx.doi.org/10.1038/s41467-022-35020-y |
Sumario: | Improved response to canonical therapies requires a mechanistic understanding of dynamic tumor heterogeneity by identifying discrete cellular populations with enhanced cellular plasticity. We have previously demonstrated distinct resistance mechanisms in skin basal cell carcinomas, but a comprehensive understanding of the cellular states and markers associated with these populations remains poorly understood. Here we identify a pre-existing resistant cellular population in naive basal cell carcinoma tumors marked by the surface marker LY6D. LY6D(+) tumor cells are spatially localized and possess basal cell carcinoma and squamous cell carcinoma-like features. Using computational tools, organoids, and spatial tools, we show that LY6D(+) basosquamous cells represent a persister population lying on a central node along the skin lineage-associated spectrum of epithelial states with local environmental and applied therapies determining the kinetics of accumulation. Surprisingly, LY6D(+) basosquamous populations exist in many epithelial tumors, such as pancreatic adenocarcinomas, which have poor outcomes. Overall, our results identify the resistant LY6D(+) basosquamous population as an important clinical target and suggest strategies for future therapeutic approaches to target them. |
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