Osteosarcoma tumors maintain intra-tumoral transcriptional heterogeneity during bone and lung colonization.

Autor: Rajan S; Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA.; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Franz EM; Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA.; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., McAloney CA; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA., Vetter TA; Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Cam M; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Gross AC; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Taslim C; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Wang M; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Cannon MV; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Oles A; Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA., Roberts RD; Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA. Ryan.Roberts@nationwidechildrens.org.; Division of Pediatric Hematology, Oncology, and BMT, Nationwide Children's Hospital, Columbus, OH, USA. Ryan.Roberts@nationwidechildrens.org.; The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA. Ryan.Roberts@nationwidechildrens.org.
Jazyk: angličtina
Zdroj: BMC biology [BMC Biol] 2023 Apr 27; Vol. 21 (1), pp. 98. Date of Electronic Publication: 2023 Apr 27.
DOI: 10.1186/s12915-023-01593-3
Abstrakt: Background: Tumors are complex tissues containing collections of phenotypically diverse malignant and nonmalignant cells. We know little of the mechanisms that govern heterogeneity of tumor cells nor of the role heterogeneity plays in overcoming stresses, such as adaptation to different microenvironments. Osteosarcoma is an ideal model for studying these mechanisms-it exhibits widespread inter- and intra-tumoral heterogeneity, predictable patterns of metastasis, and a lack of clear targetable driver mutations. Understanding the processes that facilitate adaptation to primary and metastatic microenvironments could inform the development of therapeutic targeting strategies.
Results: We investigated single-cell RNA-sequencing profiles of 47,977 cells obtained from cell line and patient-derived xenograft models as cells adapted to growth within primary bone and metastatic lung environments. Tumor cells maintained phenotypic heterogeneity as they responded to the selective pressures imposed during bone and lung colonization. Heterogenous subsets of cells defined by distinct transcriptional profiles were maintained within bone- and lung-colonizing tumors, despite high-level selection. One prominent heterogenous feature involving glucose metabolism was clearly validated using immunofluorescence staining. Finally, using concurrent lineage tracing and single-cell transcriptomics, we found that lung colonization enriches for multiple clones with distinct transcriptional profiles that are preserved across cellular generations.
Conclusions: Response to environmental stressors occurs through complex and dynamic phenotypic adaptations. Heterogeneity is maintained, even in conditions that enforce clonal selection. These findings likely reflect the influences of developmental processes promoting diversification of tumor cell subpopulations, which are retained, even in the face of selective pressures.
(© 2023. The Author(s).)
Databáze: MEDLINE
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