Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution

Aynaud, Marie-Ming; Mirabeau, Olivier; Gruel, Nadège; Grossetête, Sandrine; Boeva, Valentina; Durand, Simon; Surdez, Didier; Saulnier, Olivier; Zaïdi, Sakina; Gribkova, Svetlana; Fouché, Aziz; Kairov, Ulykbek; Raynal, Virginie; Tirode, Franck; Grünewald, Thomas G.P.; Bohec, Mylène; Baulande, Sylvain; Janoueix‐Lerosey, Isabelle; Vert, Jean-Philippe; Barillot, Emmanuel; Delattre, Olivier; Zinovyev, Andreï

doi:10.1016/j.celrep.2020.01.049

Cited by 116 publications

(133 citation statements)

References 75 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…Multiple studies have demonstrated that ectopic EWSR1-FLI1 expression leads to the expression of neuroectodermal markers in MSCs and that EWSR1-FLI1 depletion in Ewing sarcoma cells leads to increased mesenchymal gene expression patterns [13,14]. Consistent with these findings, our analysis showed that samples with lower EWSR1-FLI1 expression had higher PHATE_1 positions (more mesodermal), and samples with higher EWSR1-FLI1 expression had lower PHATE_1 positions (more pluripotent/neuroectodermal) (Figures 3 and S5).…”

Section: Discussionsupporting

confidence: 84%

“…Recent reports indicate that EWSR1-FLI1 expression levels play a role in defining tumor heterogeneity, particularly in defining proliferative and migratory subpopulations [14,20]. In the above results, we found that EWSR1-FLI1 pushes Ewing sarcoma cells along a developmental trajectory between pluripotent/neuroectodermal and mesodermal cell states.…”

Section: Phate_1 Gene Scores Identify Mesenchymal-like Cellular Subposupporting

confidence: 79%

“…In addition to EWSR1-FLI1 knock-down, there were several other interventions which significantly pushed Ewing sarcoma along this developmental trajectory ( Figure S6). It was previously reported that ectopic EWSR1-FLI1 expression induces neuroectodermal marker expression in MSCs [13] and that EWSR1-FLI1 knockdown in Ewing sarcoma cells promotes mesenchymal marker expression [14]. These findings led us to hypothesize that EWSR1-FLI1 activity controls the position of Ewing sarcoma in the pluripotent/neuroectodermal to mesodermal developmental trajectory along PHATE_1 ( Figure 2B; Video S1).…”

Section: Ewsr1-fli1 Expression Levels Determine Ewing Sarcoma's Phatementioning

confidence: 61%

“…Recent studies have demonstrated that EWSR1-FLI1 activity plays a central role in defining Ewing tumor heterogeneity [14,20]. Combining single cell transcriptomes from cell line and PDX samples, we identified a subpopulation which displayed the highest PHATE_1 score (mesodermal).…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility

Miller

Gorthi

Bassani³

et al. 2020

Cancers

View full text Add to dashboard Cite

Ewing sarcoma is an aggressive pediatric cancer of enigmatic cellular origins typically resulting from a single translocation event t (11; 22) (q24; q12). The resulting fusion gene, EWSR1-FLI1, is toxic or unstable in most primary tissues. Consequently, attempts to model Ewing sarcomagenesis have proven unsuccessful thus far, highlighting the need to identify the cellular features which permit stable EWSR1-FLI1 expression. By re-analyzing publicly available RNA-Sequencing data with manifold learning techniques, we uncovered a group of Ewing-like tissues belonging to a developmental trajectory between pluripotent, neuroectodermal, and mesodermal cell states. Furthermore, we demonstrated that EWSR1-FLI1 expression levels control the activation of these developmental trajectories within Ewing sarcoma cells. Subsequent analysis and experimental validation demonstrated that the capability to resolve R-loops and mitigate replication stress are probable prerequisites for stable EWSR1-FLI1 expression in primary tissues. Taken together, our results demonstrate how EWSR1-FLI1 hijacks developmental gene programs and advances our understanding of Ewing sarcomagenesis.

show abstract

Section: Discussionsupporting

confidence: 84%

Section: Phate_1 Gene Scores Identify Mesenchymal-like Cellular Subposupporting

confidence: 79%

Section: Ewsr1-fli1 Expression Levels Determine Ewing Sarcoma's Phatementioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility

Miller

Gorthi

Bassani³

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…While fluctuations in EWS-FLI1 levels and the ensuing consequences for YAP/TAZ signaling may be the basis for the metastatic potential of a small fraction of tumor cells in Ewing sarcoma (2% according to the postulated biomarker LOX [122]), they may not fully explain Ewing sarcoma aggressiveness. First, while there is a recent single-cell RNA-sequencing-based demonstration of cell-to-cell heterogeneity in EWS-FLI1 RNA levels associated with distinct transcriptional programs [219], direct evidence for variations in EWS-FLI1 protein levels in Ewing sarcoma is still missing. Second, there is evidence for YAP being required for sustained Ewing sarcoma cell proliferation and anchorage-independent growth [131].…”

Section: Yap/taz In Ewing Sarcomamentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

View full text Add to dashboard Cite

YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

show abstract

Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis

Yang

Chan

et al. 2023

Advanced Science

View full text Add to dashboard Cite

Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics-and complex-focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC-driven EEF1A1 expression and thus protein synthesis. High-density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient-derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy.

show abstract

Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution

Cited by 116 publications

References 75 publications

Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility

Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis

Contact Info

Product

Resources

About