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. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Extraskeletal Myxoid Chondrosarcoma: State of the Art and Current Research on Biology and Clinical Management

“…Recently, it was reported that EWSR1 - and TAF15 -translocated EMCs feature a different transcriptional profile, with the axon guidance pathway being a major discriminant. In particular, compared to the EWSR1-NR4A3 EMC subtype, TAF15-NR4A3 EMC over-expresses pro-tumorigenic axonal guidance molecules, supporting the notion that the type of NR4A3 partner dictates an axon guidance switch that affects tumor biology [ 35 ]. These findings are in agreement with some reports suggesting that TAF15-NR4A3 EMC features a more aggressive phenotype, with a high-grade morphology and plasmocytoid/rhabdoid morphology in over half of TAF15 -translocated EMCs [ 36 ].…”

“…Although the precise mechanism behind the selective activity of antiangiogenics in EMC is still undefined, the transcriptional profiling of a subset of responder and non-responder EMCs highlighted up-regulation of canonical pazopanib targets FMS-lyke tyrosine kinase 1 (FLT1/vascular endothelial growth factor receptor 1-VEGFR1), kinase insert domain receptor (KDR/vascular endothelial growth factor receptor 2-VEGFR2), FMS-lyke tyrosine kinase receptor 4 (FLT4/vascular endothelial growth factor receptor 3-VEGFR3), and cognate ligands (vascular endothelial growth factor A-VEGFA and vascular endothelial growth factor C-VEGFC), as well as components of the Notch Homolog Protein (NOTCH) pathway in the pazopanib-sensitive cohort. Intriguingly, as observed with sunitinib, all three TAF15-NR4A3 -positive tumors included in this pazopanib trial failed to respond to pazopanib, which suggests that the more malignant phenotype of the TAF15-translocated EMC may impair antiangiogenic sensitivity [ 35 ]. Eventually, a retrospective study of apatinib, a new selective inhibitor of VEGFR2 under investigation in different cancers, among which is STS, identified one partial response and two stable diseases of three EMC patients, with an interesting median duration of response of 21.2 months [ 61 ].…”

“…Overall, EMC patients who suffer distant relapse have an unfavorable prognosis and medical options available in these cases are limited, although the survival in the advanced phase is often longer than expected in other STS. Although in vitro investigations and tumor molecular profiling studies are suggesting novel potential therapeutic targets [ 10 , 35 , 45 , 46 ] ( Table 1 ), there is a strong urgency to identify prognostic factors and therapeutic strategies to improve the chance of a cure at disease onset and in case of relapse. To this end, networking is essential, as well as fostering discussions with the regulators on how to improve research and drug development in ultra-rare tumors.…”

Smoking and Family Cancer History Are Associated With Sarcomas in A Japanese Population Study

“…Leiomyosarcoma was associated with deletion of TP53 and RB1 gene and BRCA1/2 gene rearrangement [48]. EMC was correlated with NR4A3 gene rearrangement [46]. Chordoma was associated with T-boxfamily transcription factor; brachyury [49,50].…”

“…However, there have only been a few previous reports about the association between smoking and sarcoma development [22][23][24][25][26]42]. Recent genomic studies have expanded our knowledge regarding the basis of carcinogenesis, including sarcoma; however, gene abnormalities, such as fusion genes or driver mutations, in most types of sarcoma remain unclear [43][44][45][46][47][48][49][50]. Understanding the impact of lifestyle habits, lifestyle diseases, and genetic abnormalities would be helpful to advise patients on how to prevent carcinogenetic factors and also how to obtain appropriate genetic counseling.…”