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Keywords: osteosarcoma; therapy; metastatic colonization; EMT; ZEB1; bone development Abstract Osteosarcoma is an often-fatal mesenchyme-derived malignancy in children and young adults. Overexpression of EMT-transcription factors (EMT-TFs) has been associated with poor clinical outcome. Here, we demonstrated that the EMT-TF ZEB1 is able to block osteoblastic differentiation in normal bone development as well as in osteosarcoma cells. Consequently, overexpression of ZEB1 in osteosarcoma characterizes poorly differentiated, highly metastatic subgroups and its depletion induces differentiation of osteosarcoma cells. Overexpression of ZEB1 in osteosarcoma is frequently associated with silencing of the imprinted DLK-DIO3 locus, which encodes for microRNAs targeting ZEB1. Epigenetic reactivation of this locus in osteosarcoma cells reduces ZEB1 expression, induces differentiation, and sensitizes to standard treatment, thus indicating therapeutic options for ZEB1-driven osteosarcomas. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. Article Note: Equal first authors..sup. These authors contributed equally to this work. CAPTION(S): Supplementary materials and methods Figure S1. ZEB1 is elevated in osteosarcoma and correlates with progression and poor survival Figure S2. ZEB1 regulates osteoblastic differentiation in mesenchymal stem cells and in osteosarcoma cells Figure S3. ZEB1 facilitates tumorigenic traits of osteosarcoma cells in vitro and in vivo Figure S4. ZEB1 expression is linked to the frequently inactivated DLK1-DIO3 locus in osteosarcoma Figure S5. Loss of imprinting at the DLK1-DIO3 locus enables indirect epigenetic targeting of ZEB1-driven osteosarcomas Table S1. pre-miRNAs and miRNA inhibitors Table S2. Oligonucleotides used Table S3. Plasmids and constructs used Byline: Manuel Ruh, Marc P Stemmler, Isabell Frisch, Kathrin Fuchs, Ruthger Roey, Julia Kleemann, Maike Roas, Harald Schuhwerk, Rebecca L Eccles, Abbas Agaimy, Daniel Baumhoer, Geert Berx, Fabian Müller, Thomas Brabletz, Simone Brabletz