VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

Watson, Sarah; LaVigne, Collette A; Xu, Lin; Surdez, Didier; Cyrta, Joanna; Calderon, Delia; Cannon, Matthew; Kent, Matthew R.; Silvius, Katherine M; Kucinski, Jack P.; Harrison, Emma N; Murchison, Whitney; Rakheja, Dinesh; Tirode, Franck; Delattre, Olivier; Amatruda, James F.; Kendall, Genevieve C.

doi:10.1016/j.celrep.2023.112013

Cited by 9 publications

(7 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To test whether VGLL2-NCOA2 and TEAD1-NCOA2-mediated sarcomagenesis is CBP/p300 dependent, we utilized the C2C12 myoblast transformation models both in vitro and in vivo . Prior report has demonstrated that VGLL2-NCOA2 can induce oncogenic transformation of C2C12 cells in cell culture and in allograft mouse tumor models (Watson et al, 2023). However, it is not known whether VGLL2-NCOA2 or TEAD1-NCOA2 can induce TEAD-mediated transcription and whether p300 is functionally relevant in these models.…”

Section: Resultsmentioning

confidence: 99%

“…002019, Shanghai, China). C2C12-control, C2C12-VGLL2-NCOA2, and C2C12-TEAD1-NCOA2 cell lines were utilized in allograft experiments adapted from Watson et al (Watson et al, 2023). Five million cells were resuspended in 100 μL of sterile PBS and injected intramuscularly into the leg of nude mice under anesthesia.…”

Section: Methodsmentioning

confidence: 99%

“…In these fusions, VGLL2 and TEAD1 participate as 5’partners in the recurrent translocations, and their 3’fusion partners often involve the NCOA2 gene on 8q13.3 (Alaggio et al, 2016). Among these fusion proteins, the VGLL2-NCOA2 fusion has recently been shown to be able to drive tumor formation in zebrafish and allograft models (Watson et al, 2023). Here, we explored the molecular mechanism underlying the oncogenic transformation of VGLL2-NCOA2 and TEAD1-NCOA2 fusion proteins.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300

Guo,

Hu,

Cotton

et al. 2024

Preprint

View full text Add to dashboard Cite

Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEAD. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. We demonstrate that, in contrast to VGLL2 and TEAD1, the fusion proteins are strong activators of TEAD-dependent transcription, and their function does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase p300 to control TEAD-mediated transcriptional and epigenetic landscapes. We showed that small molecule p300 inhibition can suppress fusion proteins-induced oncogenic transformation bothin vitroandin vivo. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300

Guo,

Hu,

Cotton

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…As the Zebrafish RMS models histologically and molecularly recapitulate the human sarcoma, these systems can be useful to identify and evaluate therapeutic vulnerabilities and prognostic biomarkers. In agreement, ARF6 has been described as an actionable vulnerability for VGLL2-NCOA2 driven RMS (Watson et al, 2023) and HES3 as prognostic marker and a mediator of PAX3-FOXO1 tumorigenesis (Kendall et al, 2018). Exciting translational animal models have been developed over the course of several decades, allowing for mechanistic studies of sarcomagenesis, including diverse mouse syngeneic models (Keller et al, 2004a;Keller et al, 2004b;Searcy et al, 2023) and mouse xenograft models (Patel et al, 2022;Wei et al, 2022).…”

Section: Animal Modeling For In Vivo Sarcoma Etiologymentioning

confidence: 97%

Epigenetic determinants of fusion-driven sarcomas: paradigms and challenges

Stanton,

Pomella

2024

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

We describe exciting recent advances in fusion-driven sarcoma etiology, from an epigenetics perspective. By exploring the current state of the field, we identify and describe the central mechanisms that determine sarcomagenesis. Further, we discuss seminal studies in translational genomics, which enabled epigenetic characterization of fusion-driven sarcomas. Important context for epigenetic mechanisms include, but are not limited to, cell cycle and metabolism, core regulatory circuitry, 3-dimensional chromatin architectural dysregulation, integration with ATP-dependent chromatin remodeling, and translational animal modeling. Paradoxically, while the genetic requirements for oncogenic transformation are highly specific for the fusion partners, the epigenetic mechanisms we as a community have uncovered are categorically very broad. This dichotomy prompts the question of whether the investigation of rare disease epigenomics should prioritize studying individual cell populations, thereby examining whether the mechanisms of chromatin dysregulation are specific to a particular tumor. We review recent advances focusing on rhabdomyosarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, undifferentiated round cell sarcoma, Ewing sarcoma, myxoid/round liposarcoma, epithelioid hemangioendothelioma and desmoplastic round cell tumor. The growing number of groundbreaking discoveries in the field, motivated us to anticipate further exciting advances in the area of mechanistic epigenomics and direct targeting of fusion transcription factors in the years ahead.

show abstract

“…Loss and gain-of-function approaches in a cell culture context can be leveraged to define genetic cooperation and the resulting phenotypic outcomes. To this end, overexpression or knockdown of putative oncogenes and cooperating genes has led to important discoveries in how they may be functioning in cancer cells [1][2][3][4][5]. However, typically, this type of modeling does not account for critical factors in the tumorigenic process, including timing of expression, the level and duration of expression, or cessation of expression.…”

Section: Introductionmentioning

confidence: 99%

New Dual Inducible Cellular Model to Investigate Temporal Control of Oncogenic Cooperating Genes

Kent,

Jay,

Kendall

2024

Preprint

Self Cite

View full text Add to dashboard Cite

The study of cooperating genes in cancer can lead to mechanistic understanding and identifying potential therapeutic targets. To facilitate these types of studies, we developed a new dual-inducible system utilizing the tetracycline- and cumate-inducible systems driving HES3 and the PAX3::FOXO1 fusion-oncogene, respectively, as cooperating genes from fusion-positive rhabdomyosarcoma. With this new model, we can independently induce expression of either HES3 or PAX3::FOXO1, as well as simultaneously induce expression of both genes. This new model will allow us to further investigate the cooperation between HES3 and PAX3::FOXO1 including the temporal requirements for genetic cooperation. This dual-inducible model can be adapted for any cooperating genes, allowing for independent, simultaneous, or temporally controlled gene expression.

show abstract

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

Cited by 9 publications

References 77 publications

VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300

VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300

Epigenetic determinants of fusion-driven sarcomas: paradigms and challenges

New Dual Inducible Cellular Model to Investigate Temporal Control of Oncogenic Cooperating Genes

Contact Info

Product

Resources

About