NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas

Monica Brenca, Silvia Stacchiotti, Kelly Fassetta, Marta Sbaraglia, Milijana Janjusevic, Dominga Racanelli, Maurizio Polano, Sabrina Rossi, Silvia Brich, Gian P Dagrada, Paola Collini, Chiara Colombo, Alessandro Gronchi, Annalisa Astolfi, Valentina Indio, Maria A Pantaleo, Piero Picci, Paolo G Casali, Angelo P Dei Tos, Silvana PilottiRoberta Maestro

Research output: Contribution to journalArticle

Abstract

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma histotype with uncertain differentiation. EMC is hallmarked by the rearrangement of the NR4A3 gene, which in most cases fuses with EWSR1 or TAF15. TAF15-translocated EMC seem to feature a more aggressive course compared to EWSR1-positive EMCs, but whether the type of NR4A3 chimera impinges upon EMC biology is still largely undefined. To gain insights on this issue, a series of EMC samples (7 EWSR1-NR4A3 and 5 TAF15-NR4A3) were transcriptionally profiled. Our study unveiled that the two EMC variants display a distinct transcriptional profile and that the axon guidance pathway is a major discriminant. In particular, class 4-6 semaphorins and axonal guidance cues endowed with pro-tumorigenic activity were more expressed in TAF15-NR4A3 tumors; vice versa, class 3 semaphorins, considered to convey growth inhibitory signals, were more abundant in EWSR1-NR4A3 EMC. Intriguingly, the dichotomy in axon guidance signaling observed in the two tumor variants was recapitulated in in vitro cell models engineered to ectopically express EWSR1-NR4A3 or TAF15-NR4A3. Moreover, TAF15-NR4A3 cells displayed a more pronounced tumorigenic potential, as assessed by anchorage-independent growth. Overall, our results indicate that the type of NR4A3 chimera dictates an axon guidance switch and impacts on tumor cell biology. These findings may provide a framework for interpretation of the different clinical-pathological features of the two EMC variants and lay down the bases for the development of novel patient stratification criteria and therapeutic approaches. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Original languageEnglish
Pages (from-to)90-101
Number of pages12
JournalJournal of Pathology
Volume249
Issue number1
DOIs
Publication statusPublished - Sep 2019

Keywords

  • EWSR1
  • NR4A3
  • TAF15
  • axon guidance
  • extraskeletal myxoid chondrosarcomas
  • sarcoma
  • transcriptional profile

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