Unveiling the molecular pathogenesis of chordoma: a new paradigm for molecular targeting of rare cancers

Tos, Angelo Paolo Dei

doi:10.1002/path.2847

Cited by 10 publications

(3 citation statements)

References 9 publications

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“…It may also account for the limited value of single targeted therapies in patients with chordoma, for example antagonists to EGFR, and ckit/PDGFR , , . Given this background, and that chordoma has a poor prognosis with limited therapeutic options , we consider that targeting brachyury directly using RNA interference‐mediated gene therapy, or other methodologies , has a biologically justifiable rationale.…”

Section: Discussionmentioning

confidence: 99%

An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma

Nelson

Pillay

Henderson

et al. 2012

The Journal of Pathology

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Chordoma is a rare malignant tumour of bone, the molecular marker of which is the expression of the transcription factor, brachyury. Having recently demonstrated that silencing brachyury induces growth arrest in a chordoma cell line, we now seek to identify its downstream target genes. Here we use an integrated functional genomics approach involving shRNA-mediated brachyury knockdown, gene expression microarray, ChIP-seq experiments, and bioinformatics analysis to achieve this goal. We confirm that the T-box binding motif of human brachyury is identical to that found in mouse, Xenopus, and zebrafish development, and that brachyury acts primarily as an activator of transcription. Using human chordoma samples for validation purposes, we show that brachyury binds 99 direct targets and indirectly influences the expression of 64 other genes, thereby acting as a master regulator of an elaborate oncogenic transcriptional network encompassing diverse signalling pathways including components of the cell cycle, and extracellular matrix components. Given the wide repertoire of its active binding and the relative specific localization of brachyury to the tumour cells, we propose that an RNA interference-based gene therapy approach is a plausible therapeutic avenue worthy of investigation.

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Section: Discussionmentioning

confidence: 99%

An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma

Nelson

Pillay

Henderson

et al. 2012

The Journal of Pathology

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“…Presneau et al (50) and Dei Tos (53) demonstrated that close to half of the investigated chordoma cases showed a gain of chromosome band 6q27 (the locus wherein BRACHYURY locates) either through polysomy of the entire chromosome 6 or structural rearrangements, which indicates that cCNGs of BRACHYURY are pathogenetically relevant in sporadic chordoma. Cho et al (35) and Pillay et al (54) demonstrated that a common single-nucleotide polymorphism (SNP) located in the BRACHYURY gene, rs2305089, has strong association with the risk of sporadic chordoma.…”

Section: The Genetic Basis Of Brachyury Expression In Chordomamentioning

confidence: 98%

The Roles of Embryonic Transcription Factor BRACHYURY in Tumorigenesis and Progression

Chen

Zhang

et al. 2020

Front. Oncol.

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Transcription factor brachyury, with a DNA-binding T-domain, regulates posterior mesoderm formation and notochord development through binding with highly conserved palindromic consensus sequence in a variety of organisms. The absence of brachyury expression in majority of adult normal tissues and exclusive tumor-specific expression provides the potential to be developed into a novel and promising diagnostic and therapeutic target in cancer. As a sensitive and specific marker in the diagnosis of chordoma, brachyury protein has been verified to involve in the process of carcinogenesis and progression of chordoma and several epithelial carcinomas in various studies, but the mechanism by which brachyury promotes tumor cells migrate, invade and metastasis still remains less clear. To this end, we attempt to summarize the literature on the upstream regulatory pathway of brachyury transcription and downstream controlling network by brachyury activation, all of which involve in both the embryonic development and tumor progression. We present the respective correlation of brachyury expression with tumor progression, distant metastasis, survival rate and prognosis in several types of tumor samples (including chordoma, lung cancer, breast carcinoma, and prostate cancer), and various brachyury gain-of-function and loss-of-function experiments are summarized to explore its specific role in respective tumor cell line in vitro. In addition, we also discuss another two programs relating to brachyury function: epithelial-to-mesenchymal transition (EMT) and cell cycle control, both of which implicate in the regulation of brachyury on biological behavior of tumor cells. This review will provide an overview of the function of master transcriptional factor brachyury, compare the similarities and differences of its role between embryonic development and carcinogenesis, and list the evidence on which brachyury-target therapies have the potential to help control advanced cancer populations.

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“…Chordoma accounts for approximately 1-4% of all bone tumors (3) and has a population-based incidence rate of 0.8/1000000 (4). The peak age for chordoma onset ranges from 60 to 70 years (5)(6)(7)(8). Chordomas most commonly involve the sacrococcygeal or skull base (9), and cases occurring outside the axial skeleton have also been reported (10).…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological and Prognostic Characteristics in Dedifferentiated/Poorly Differentiated Chordomas: A Pooled Analysis of Individual Patient Data From 58 Studies and Comparison With Conventional Chordomas

et al. 2021

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BackgroundCurrently, the clinicopathological and prognostic characteristics of dedifferentiated chordoma (DC) and poorly differentiated chordoma (PDC) remain poorly understood. In this study, we sought to characterize clinicopathological parameters in a large PDC/DC cohort and determine their correlations with progression-free survival (PFS) and overall survival (OS) of patients. We also attempted to compare clinical features between PDC/DC and conventional chordoma (CC).MethodsLiterature searches (from inception to June 01, 2020) using Medline, Embase, Google Scholar and Wanfang databases were conducted to identify eligible studies according to predefined criteria. The local database at our center was also retrospectively reviewed to include CC patients for comparative analysis.ResultsFifty-eight studies from the literature and 90 CC patients from our local institute were identified; in total, 54 PDC patients and 96 DC patients were analyzed. Overall, PDC or DC had distinct characteristics from CC, while PDC and DC shared similar clinical features. Adjuvant radiotherapy and chemotherapy were associated with both PFS and OS in PDC patients in the univariate and/or multivariate analyses. In the DC cohort, tumor resection type, adjuvant chemotherapy and tumor dedifferentiation components significantly affected PFS, whereas none of them were predictive of outcome in the multivariate analysis. By analyzing OS, we found that surgery, resection type and the time to dedifferentiation predicted the survival of DC patients; however, only surgery remained significant after adjusting for other covariables.ConclusionsThese data may offer useful information to better understand the clinical characteristics of PDC/DC and may be helpful in improving the outcome prediction of patients.

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Unveiling the molecular pathogenesis of chordoma: a new paradigm for molecular targeting of rare cancers

Cited by 10 publications

References 9 publications

An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma

An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma

The Roles of Embryonic Transcription Factor BRACHYURY in Tumorigenesis and Progression

Clinicopathological and Prognostic Characteristics in Dedifferentiated/Poorly Differentiated Chordomas: A Pooled Analysis of Individual Patient Data From 58 Studies and Comparison With Conventional Chordomas

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