1. Mapping the Single-Cell Differentiation Landscape of Osteosarcoma.
- Author
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Truong DD, Weistuch C, Murgas KA, Admane P, King BL, Chauviere Lee J, Lamhamedi-Cherradi SE, Swaminathan J, Daw NC, Gordon N, Gopalakrishnan V, Gorlick RG, Somaiah N, Deasy JO, Mikos AG, Tannenbaum A, and Ludwig J
- Subjects
- Humans, Single-Cell Analysis methods, Transcriptome, Cell Lineage genetics, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Gene Expression Profiling, Osteosarcoma pathology, Osteosarcoma genetics, Osteosarcoma mortality, Cell Differentiation, Mesenchymal Stem Cells pathology, Mesenchymal Stem Cells metabolism, Bone Neoplasms pathology, Bone Neoplasms genetics, Bone Neoplasms mortality
- Abstract
Purpose: The genetic intratumoral heterogeneity observed in human osteosarcomas poses challenges for drug development and the study of cell fate, plasticity, and differentiation, which are processes linked to tumor grade, cell metastasis, and survival., Experimental Design: To pinpoint errors in osteosarcoma differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directs mesenchymal stem cells toward adipogenic and osteoblastic fates. Incorporating preexisting chondrocyte data, we applied trajectory analysis and non-negative matrix factorization to generate the first human mesenchymal differentiation atlas., Results: This "roadmap" served as a reference to delineate the cellular composition of morphologically complex osteosarcoma tumors and quantify each cell's lineage commitment. Projecting a bulk RNA-sequencing osteosarcoma dataset onto this roadmap unveiled a correlation between a stem-like transcriptomic phenotype and poorer survival outcomes., Conclusions: Our study quantifies osteosarcoma differentiation and lineage, a prerequisite to better understanding lineage-specific differentiation bottlenecks that might someday be targeted therapeutically., (©2024 American Association for Cancer Research.)
- Published
- 2024
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