Meningioma transcription factors link cell lineage with systemic metabolic cues

Ziming Du, Ryan Brewster, Parker H Merrill, Juliann Chmielecki, Josh Francis, Ayal Aizer, Malak Abedalthagafi, Lynette M Sholl, Lars Geffers, Brian Alexander, Sandro Santagata

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Background: Tumor cells recapitulate cell-lineage transcriptional programs that are characteristic of normal tissues from which they arise. It is unclear why such lineage programs are fatefully maintained in tumors and if they contribute to cell proliferation and viability.

Methods: Here, we used the most common brain tumor, meningioma, which is strongly associated with female sex and high body mass index (BMI), as a model system to address these questions. We screened expression profiling data to identify the transcription factor (TF) genes which are highly enriched in meningioma, and characterized the expression pattern of those TFs and downstream genes in clinical meningioma samples as well as normal brain tissues. Meningioma patient-derived cell lines (PDCLs) were used for further validation and characterization.

Results: We identified 8 TFs highly enriched in meningioma. Expression of these TFs, which included sine oculis homeobox 1 (SIX1), readily distinguished meningiomas from other primary brain tumors and was maintained in PDCLs and even in pulmonary meningothelial nodules. In meningioma PDCLs, SIX1 and its coactivator eyes absent 2 (EYA2) supported the expression of the leptin receptor (LEPR), the cell-surface receptor for leptin (LEP), the adipose-specific hormone that is high in women and in individuals with high BMI. Notably, these transcriptional regulatory factors, LEPR and LEP, both contributed to support meningioma PDCLs proliferation and survival, elucidating a survival dependency on both a core transcriptional program and a metabolic cell-surface receptor.

Conclusions: These findings provide one rationale for why lineage TF expression is maintained in meningioma and for the epidemiological association of female sex and obesity with meningioma risk.

Original languageEnglish
Pages (from-to)1331-1343
Number of pages13
JournalNeuro-Oncology
Volume20
Issue number10
DOIs
Publication statusPublished - 3 Sept 2018
Externally publishedYes

Keywords

  • Animals
  • Apoptosis
  • Biomarkers, Tumor/genetics
  • Case-Control Studies
  • Cell Cycle
  • Cell Lineage
  • Cell Proliferation
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Homeodomain Proteins/genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics
  • Leptin/genetics
  • Male
  • Meningeal Neoplasms/genetics
  • Meningioma/genetics
  • Mice
  • Middle Aged
  • Nuclear Proteins/genetics
  • Obesity/genetics
  • Prognosis
  • Protein Tyrosine Phosphatases/genetics
  • Receptors, Immunologic/genetics
  • Receptors, Leptin/genetics
  • Receptors, Prostaglandin/genetics
  • Survival Rate
  • Tissue Array Analysis
  • Transcription Factors/genetics
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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