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Cited by 12Sarcoma Diagnosis and TreatmentMesenchymal stem cell researchCancer Cells and Metastasis

The c-Myc/TBX3 Axis Promotes Cellular Transformation of Sarcoma-Initiating Cells

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Damerell, Victoria, Ambele, Melvin Anyasi, Salisbury, Shanel, Neumann-Mufweba, Alexis, Durandt, Chrisna, Pepper, Michael Sean, Prince, Sharon·2022·Frontiers in Oncology
DOI 10.3389/fonc.2021.801691PMC PMC8821881
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Abstract

Sarcomas are highly aggressive cancers of mesenchymal origin whose clinical management is highly complex. This is partly due to a lack of understanding of the molecular mechanisms underpinning the transformation of mesenchymal stromal/stem cells (MSCs) which are presumed to be the sarcoma-initiating cells. c-Myc is amplified/overexpressed in a range of sarcomas where it has an established oncogenic role and there is evidence that it contributes to the malignant transformation of MSCs. T-box transcription factor 3 (TBX3) is upregulated by c-Myc in a host of sarcoma subtypes where it promotes proliferation, tumor formation, migration, and invasion. This study investigated whether TBX3 is a c-Myc target in human MSCs (hMSCs) and whether overexpressing TBX3 in hMSCs can phenocopy c-Myc overexpression to promote malignant transformation. Using siRNA, qRT-PCR, luciferase reporter and chromatin-immunoprecipitation assays, we show that c-Myc binds and directly activates TBX3 transcription in hMSCs at a conserved E-box motif. When hMSCs were engineered to stably overexpress TBX3 using lentiviral gene transfer and the resulting cells characterised in 2D and 3D, the overexpression of TBX3 was shown to promote self-renewal, bypass senescence, and enhance proliferation which corresponded with increased levels of cell cycle progression markers (cyclin A, cyclin B1, CDK2) and downregulation of the p14 ARF/MDM2/p53 tumor suppressor pathway. Furthermore, TBX3 promoted the migratory and invasive ability of hMSCs which associated with increased levels of markers of migration (Vimentin, SLUG, SNAIL, TWIST1) and invasion (MMP2, MMP9). Transcriptomic analysis revealed that genes upregulated upon TBX3 overexpression overlapped with c-myc targets, were involved in cell cycle progression, and were associated with sarcomagenesis. Together, the data described indicate that the c-Myc/TBX3 oncogenic molecular pathway may be a key mechanism that transforms hMSCs into sarcomas.

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Authors
Damerell, V., Ambele, M. A., Salisbury, S., Neumann-Mufweba, A., Durandt, C., Pepper, M. S., & Prince, S.
Affiliations
  • University of Cape Town (ZA)
  • South African Medical Research Council (ZA)
Corresponding author
Prince, Sharon
ORCID
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2022-01-25
Volume
11
Pages
801691-801691
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2021.801691
PMC
PMC8821881
OpenAlex
W4210498543
Cited by
12
References
4
Citations by year
2025: 4 · 2024: 5 · 2023: 3
FWCI
1.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UpSpace Institutional Repository (University of Pretoria) (submittedVersion, cc-by)
Funders
  • South African Medical Research Council
  • National Research Foundation
  • Cancer Association of South Africa
  • University of Cape Town
  • University of Pretoria
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
c-Myc, TBX3, sarcoma, mesenchymal stem cells, malignant transformation, cell cycle progression, p53 pathway, senescence bypass, cell migration and invasion, EMT transcription factors, sarcomagenesis, transcriptional coactivation

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