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 Paolo Dagrada, Paola Collini, Chiara Colombo, Alessandro Gronchi, Annalisa Astolfi, Valentina Indio, Maria Abbondanza Pantaleo, Piero Picci, Paolo G Casali, Angelo Paolo Dei Tos, Silvana Pilotti & 1 others Roberta 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalJournal of Pathology
DOIs
Publication statusE-pub ahead of print - Apr 25 2019

Fingerprint

Semaphorins
Proteins
Neoplasms
Axon Guidance
Extraskeletal Myxoid Chondrosarcoma
Gene Rearrangement
Growth
Sarcoma
Cues
Cell Biology
Therapeutics

Keywords

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

Cite this

NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas. / Brenca, Monica; Stacchiotti, Silvia; Fassetta, Kelly; Sbaraglia, Marta; Janjusevic, Milijana; Racanelli, Dominga; Polano, Maurizio; Rossi, Sabrina; Brich, Silvia; Dagrada, Gian Paolo; Collini, Paola; Colombo, Chiara; Gronchi, Alessandro; Astolfi, Annalisa; Indio, Valentina; Pantaleo, Maria Abbondanza; Picci, Piero; Casali, Paolo G; Tos, Angelo Paolo Dei; Pilotti, Silvana; Maestro, Roberta.

In: Journal of Pathology, 25.04.2019.

Research output: Contribution to journalArticle

Brenca, Monica ; Stacchiotti, Silvia ; Fassetta, Kelly ; Sbaraglia, Marta ; Janjusevic, Milijana ; Racanelli, Dominga ; Polano, Maurizio ; Rossi, Sabrina ; Brich, Silvia ; Dagrada, Gian Paolo ; Collini, Paola ; Colombo, Chiara ; Gronchi, Alessandro ; Astolfi, Annalisa ; Indio, Valentina ; Pantaleo, Maria Abbondanza ; Picci, Piero ; Casali, Paolo G ; Tos, Angelo Paolo Dei ; Pilotti, Silvana ; Maestro, Roberta. / NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas. In: Journal of Pathology. 2019.
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title = "NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas",
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. This article is protected by copyright. All rights reserved.",
keywords = "EWSR1, NR4A3, TAF15, axon guidance, extraskeletal myxoid chondrosarcomas, sarcoma, transcriptional profile",
author = "Monica Brenca and Silvia Stacchiotti and Kelly Fassetta and Marta Sbaraglia and Milijana Janjusevic and Dominga Racanelli and Maurizio Polano and Sabrina Rossi and Silvia Brich and Dagrada, {Gian Paolo} and Paola Collini and Chiara Colombo and Alessandro Gronchi and Annalisa Astolfi and Valentina Indio and Pantaleo, {Maria Abbondanza} and Piero Picci and Casali, {Paolo G} and Tos, {Angelo Paolo Dei} and Silvana Pilotti and Roberta Maestro",
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year = "2019",
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T1 - NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas

AU - Brenca, Monica

AU - Stacchiotti, Silvia

AU - Fassetta, Kelly

AU - Sbaraglia, Marta

AU - Janjusevic, Milijana

AU - Racanelli, Dominga

AU - Polano, Maurizio

AU - Rossi, Sabrina

AU - Brich, Silvia

AU - Dagrada, Gian Paolo

AU - Collini, Paola

AU - Colombo, Chiara

AU - Gronchi, Alessandro

AU - Astolfi, Annalisa

AU - Indio, Valentina

AU - Pantaleo, Maria Abbondanza

AU - Picci, Piero

AU - Casali, Paolo G

AU - Tos, Angelo Paolo Dei

AU - Pilotti, Silvana

AU - Maestro, Roberta

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/4/25

Y1 - 2019/4/25

N2 - 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. This article is protected by copyright. All rights reserved.

AB - 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. This article is protected by copyright. All rights reserved.

KW - EWSR1

KW - NR4A3

KW - TAF15

KW - axon guidance

KW - extraskeletal myxoid chondrosarcomas

KW - sarcoma

KW - transcriptional profile

U2 - 10.1002/path.5284

DO - 10.1002/path.5284

M3 - Article

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

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