Ziming Du1, Ryan Brewster1, Parker H Merrill1, Juliann Chmielecki2,3,4, Josh Francis2,3,4, Ayal Aizer2,5, Malak Abedalthagafi1,2,6, Lynette M Sholl1,2, Lars Geffers7, Brian Alexander2,5, Sandro Santagata1,2,8. 1. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. 2. Harvard Medical School, Boston, Massachusetts, USA. 3. Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 5. Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts, USA. 6. Department of Pathology, King Fahad Medical City, Riyadh, Saudi Arabia. 7. Department of Genes and Behavior, Max-Planck-Institute of Biophysical Chemistry, Goettingen, Germany. 8. Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
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.
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.
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