Abstract
Osteosarcoma (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.
Highlights
Osteosarcoma (OS) is the most common bone sarcoma and a leading cause of cancer deaths in adolescents and young adults [1, 2]
Tumors develop in the left lung by direct extension. They can only reach the right side when cells migrate from the left-sided lung tumors, intravasate into the bioreactor-perfused pulmonary vessels as derived circulating tumor cells (dCTCs), and lodge within the contralateral lung capillary network
Like lung cancer cells placed through the trachea [63], OS cells spread throughout the lung to form distinct, rapidly growing nodules that can reach ≥1 cm in size
Summary
Osteosarcoma (OS) is the most common bone sarcoma and a leading cause of cancer deaths in adolescents and young adults [1, 2]. High-grade poorly differentiated sarcomas are significantly more proliferative, invasive, and metastasis-prone than their low-grade counterparts. In light of the broad sweeping effect that tumor grade and differentiation have upon cell invasion and metastasis, it comes as no surprise that many cancer hallmarks defined by Hanahan and Weinberg are intricately linked to cell fate [9, 10]. Among the hallmarks of interest to our current studies, chemoresistance, genome instability, migratory potential, and invasiveness have all been associated with cancer stem cells (CSCs) [11, 12]. The relationship between cell fate, differentiation, and cancer hallmarks in OS is far less studied, and it remains to be determined whether dedifferentiated OS cells become, or just phenocopy, CSCs
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