Transcriptional activators YAP/TAZ and AXL orchestrate dedifferentiation, cell fate, and metastasis in human osteosarcoma

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dc.citation.journalTitleCancer Gene Therapy
dc.contributor.authorLamhamedi-Cherradi, Salah-Eddine
dc.contributor.authorMohiuddin, Sana
dc.contributor.authorMishra, Dhruva K.
dc.contributor.authorKrishnan, Sandhya
dc.contributor.authorVelasco, Alejandra Ruiz
dc.contributor.authorVetter, Amelia M.
dc.contributor.authorPence, Kristi
dc.contributor.authorMcCall, David
dc.contributor.authorTruong, Danh D.
dc.contributor.authorCuglievan, Branko
dc.contributor.authorMenegaz, Brian A.
dc.contributor.authorUtama, Budi
dc.contributor.authorDaw, Najat C.
dc.contributor.authorMolina, Eric R.
dc.contributor.authorZielinski, Rafal J.
dc.contributor.authorLivingston, John A.
dc.contributor.authorGorlick, Richard
dc.contributor.authorMikos, Antonios G.
dc.contributor.authorKim, Min P.
dc.contributor.authorLudwig, Joseph A.
dc.date.accessioned2021-07-30T15:21:23Z
dc.date.available2021-07-30T15:21:23Z
dc.date.issued2021
dc.description.abstractOsteosarcoma (OS) is a molecularly heterogeneous, aggressive, poorly differentiated pediatric bone cancer that frequently spreads to the lung. Relatively little is known about phenotypic and epigenetic changes that promote lung metastases. To identify key drivers of metastasis, we studied human CCH-OS-D OS cells within a previously described rat acellular lung (ACL) model that preserves the native lung architecture, extracellular matrix, and capillary network. This system identified a subset of cells—termed derived circulating tumor cells (dCTCs)—that can migrate, intravasate, and spread within a bioreactor-perfused capillary network. Remarkably, dCTCs highly expressed epithelial-to-mesenchymal transition (EMT)-associated transcription factors (EMT-TFs), such as ZEB1, TWIST, and SOX9, which suggests that they undergo cellular reprogramming toward a less differentiated state by coopting the same epigenetic machinery used by carcinomas. Since YAP/TAZ and AXL tightly regulate the fate and plasticity of normal mesenchymal cells in response to microenvironmental cues, we explored whether these proteins contributed to OS metastatic potential using an isogenic pair of human OS cell lines that differ in AXL expression. We show that AXL inhibition significantly reduced the number of MG63.2 pulmonary metastases in murine models. Collectively, we present a laboratory-based method to detect and characterize a pure population of dCTCs, which provides a unique opportunity to study how OS cell fate and differentiation contributes to metastatic potential. Though the important step of clinical validation remains, our identification of AXL, ZEB1, and TWIST upregulation raises the tantalizing prospect that EMT-TF-directed therapies might expand the arsenal of therapies used to combat advanced-stage OS.
dc.identifier.citationLamhamedi-Cherradi, Salah-Eddine, Mohiuddin, Sana, Mishra, Dhruva K., et al.. "Transcriptional activators YAP/TAZ and AXL orchestrate dedifferentiation, cell fate, and metastasis in human osteosarcoma." <i>Cancer Gene Therapy,</i> (2021) Springer Nature: https://doi.org/10.1038/s41417-020-00281-6.
dc.identifier.digitals41417-020-00281-6
dc.identifier.doihttps://doi.org/10.1038/s41417-020-00281-6
dc.identifier.urihttps://hdl.handle.net/1911/111048
dc.language.isoeng
dc.publisherSpringer Nature
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleTranscriptional activators YAP/TAZ and AXL orchestrate dedifferentiation, cell fate, and metastasis in human osteosarcoma
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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