Ashley M Fuller1, Ann DeVine1, Ileana Murazzi1, Nicola J Mason2, Kristy Weber3, T S Karin Eisinger-Mathason4. 1. Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, Penn Sarcoma Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 2. Department of Clinical Sciences and Advanced Medicine, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. 3. Penn Sarcoma Program, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 4. Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, Penn Sarcoma Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. karineis@pennmedicine.upenn.edu.
Abstract
PURPOSE: Undifferentiated pleomorphic sarcoma (UPS), an aggressive subtype of soft-tissue sarcoma (STS), is exceedingly rare in humans and lacks effective, well-tolerated therapies. In contrast, STS are relatively common in canine companion animals. Thus, incorporation of veterinary patients into studies of UPS offers an exciting opportunity to develop novel therapeutic strategies for this rare human disease. Genome-wide studies have demonstrated that UPS is characterized by aberrant patterns of DNA methylation. However, the mechanisms and impact of this epigenetic modification on UPS biology and clinical behavior are poorly understood. METHODS: DNA methylation in mammalian cells is catalyzed by the canonical DNA methyltransferases DNMT1, DNMT3A and DNMT3B. Therefore, we leveraged cell lines and tissue specimens from human and canine patients, together with an orthotopic murine model, to probe the functional and clinical significance of DNMTs in UPS. RESULTS: We found that the DNA methyltransferase DNMT3B is overexpressed in UPS relative to normal mesenchymal tissues and is associated with a poor prognosis. Consistent with these findings, genetic DNMT3B depletion strongly inhibited UPS cell proliferation and tumor progression. However, existing hypomethylating agents, including the clinically approved drug 5-aza-2'-deoxycytidine (DAC) and the DNMT3B-inhibiting tool compound nanaomycin A, were ineffective in UPS due to cellular uptake and toxicity issues. CONCLUSIONS: DNMT3B represents a promising molecular susceptibility in UPS, but further development of DNMT3B-targeting strategies for these patients is required.
PURPOSE: Undifferentiated pleomorphic sarcoma (UPS), an aggressive subtype of soft-tissue sarcoma (STS), is exceedingly rare in humans and lacks effective, well-tolerated therapies. In contrast, STS are relatively common in canine companion animals. Thus, incorporation of veterinary patients into studies of UPS offers an exciting opportunity to develop novel therapeutic strategies for this rare human disease. Genome-wide studies have demonstrated that UPS is characterized by aberrant patterns of DNA methylation. However, the mechanisms and impact of this epigenetic modification on UPS biology and clinical behavior are poorly understood. METHODS: DNA methylation in mammalian cells is catalyzed by the canonical DNA methyltransferases DNMT1, DNMT3A and DNMT3B. Therefore, we leveraged cell lines and tissue specimens from human and canine patients, together with an orthotopic murine model, to probe the functional and clinical significance of DNMTs in UPS. RESULTS: We found that the DNA methyltransferase DNMT3B is overexpressed in UPS relative to normal mesenchymal tissues and is associated with a poor prognosis. Consistent with these findings, genetic DNMT3B depletion strongly inhibited UPS cell proliferation and tumor progression. However, existing hypomethylating agents, including the clinically approved drug 5-aza-2'-deoxycytidine (DAC) and the DNMT3B-inhibiting tool compound nanaomycin A, were ineffective in UPS due to cellular uptake and toxicity issues. CONCLUSIONS: DNMT3B represents a promising molecular susceptibility in UPS, but further development of DNMT3B-targeting strategies for these patients is required.
Authors: Christian Koelsche; Daniel Schrimpf; Damian Stichel; Martin Sill; Felix Sahm; David E Reuss; Mirjam Blattner; Barbara Worst; Christoph E Heilig; Katja Beck; Peter Horak; Simon Kreutzfeldt; Elke Paff; Sebastian Stark; Pascal Johann; Florian Selt; Jonas Ecker; Dominik Sturm; Kristian W Pajtler; Annekathrin Reinhardt; Annika K Wefers; Philipp Sievers; Azadeh Ebrahimi; Abigail Suwala; Francisco Fernández-Klett; Belén Casalini; Andrey Korshunov; Volker Hovestadt; Felix K F Kommoss; Mark Kriegsmann; Matthias Schick; Melanie Bewerunge-Hudler; Till Milde; Olaf Witt; Andreas E Kulozik; Marcel Kool; Laura Romero-Pérez; Thomas G P Grünewald; Thomas Kirchner; Wolfgang Wick; Michael Platten; Andreas Unterberg; Matthias Uhl; Amir Abdollahi; Jürgen Debus; Burkhard Lehner; Christian Thomas; Martin Hasselblatt; Werner Paulus; Christian Hartmann; Ori Staszewski; Marco Prinz; Jürgen Hench; Stephan Frank; Yvonne M H Versleijen-Jonkers; Marije E Weidema; Thomas Mentzel; Klaus Griewank; Enrique de Álava; Juan Díaz Martín; Miguel A Idoate Gastearena; Kenneth Tou-En Chang; Sharon Yin Yee Low; Adrian Cuevas-Bourdier; Michel Mittelbronn; Martin Mynarek; Stefan Rutkowski; Ulrich Schüller; Viktor F Mautner; Jens Schittenhelm; Jonathan Serrano; Matija Snuderl; Reinhard Büttner; Thomas Klingebiel; Rolf Buslei; Manfred Gessler; Pieter Wesseling; Winand N M Dinjens; Sebastian Brandner; Zane Jaunmuktane; Iben Lyskjær; Peter Schirmacher; Albrecht Stenzinger; Benedikt Brors; Hanno Glimm; Christoph Heining; Oscar M Tirado; Miguel Sáinz-Jaspeado; Jaume Mora; Javier Alonso; Xavier Garcia Del Muro; Sebastian Moran; Manel Esteller; Jamal K Benhamida; Marc Ladanyi; Eva Wardelmann; Cristina Antonescu; Adrienne Flanagan; Uta Dirksen; Peter Hohenberger; Daniel Baumhoer; Wolfgang Hartmann; Christian Vokuhl; Uta Flucke; Iver Petersen; Gunhild Mechtersheimer; David Capper; David T W Jones; Stefan Fröhling; Stefan M Pfister; Andreas von Deimling Journal: Nat Commun Date: 2021-01-21 Impact factor: 17.694
Authors: Nicole M Merritt; Colleen A Fullenkamp; Sarah L Hall; Qining Qian; Chandni Desai; Jon Thomason; Allyn M Lambertz; Adam J Dupuy; Benjamin Darbro; Munir R Tanas Journal: Oncotarget Date: 2018-08-03