SFRP2 induces a mesenchymal subtype transition by suppression of SOX2 in glioblastoma

• Published in: Oncogene 2021-08, Vol.40 (32), p.5066-5080
• Main Authors: Guo, Min, Goudarzi, Kaveh M., Abedi, Shiva, Pieber, Melanie, Sjöberg, Elin, Behnan, Jinan, Zhang, Xing-Mei, Harris, Robert A., Bartek, Jiri, Lindström, Mikael S., Nistér, Monica, Hägerstrand, Daniel
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/109; 13/2; 13/95; 38/39; 38/77; 38/91; 42/109; 42/89; 631/67/1922; 631/67/2329; AKT protein; Apoptosis; Brain cancer; Cancer; Carrier Proteins; Cell Biology; Cell Line, Tumor; Cell proliferation; Development and progression; Epithelial-Mesenchymal Transition - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic aspects; Glioblastoma; Glioblastoma - etiology; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma multiforme; Glioma cells; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; KLF4 protein; Kruppel-Like Factor 4 - metabolism; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mesenchyme; Oncology; Oncology, Experimental; Organ Specificity; Protein Binding; Proto-Oncogene Proteins c-akt - metabolism; Quorum sensing; Receptors, Platelet-Derived Growth Factor - metabolism; Signal Transduction; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Stem cells; Wnt protein
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-021-01825-2

Intratumoral heterogeneity is a characteristic of glioblastomas that contain an intermixture of cell populations displaying different glioblastoma subtype gene expression signatures. Proportions of these populations change during tumor evolution, but the occurrence and regulation of glioblastoma subtype transition is not well described. To identify regulators of glioblastoma subtypes we utilized a combination of in vitro experiments and in silico analyses, using experimentally generated as well as publicly available data. Through this combined approach SOX2 was identified to confer a proneural glioblastoma subtype gene expression signature. SFRP2 was subsequently identified as a SOX2- antagonist, able to induce a mesenchymal glioblastoma subtype signature. A subset of patient glioblastoma samples with high SFRP2 and low SOX2 expression was particularly enriched with mesenchymal subtype samples. Phenotypically, SFRP2 decreased tumor sphere formation, stemness as assessed by limiting dilution assay, and overall cell proliferation but increased cell motility, whereas SOX2 induced the opposite effects. Furthermore, an SFRP2/non-canonical-WNT/KLF4/PDGFR/phospho-AKT/SOX2 signaling axis was found to be involved in the mesenchymal transition. Analysis of human tumor tissue spatial gene expression patterns showed distinct expression of SFRP2 - and S OX2- correlated genes in vascular and cellular areas, respectively. Finally, conditioned media from SFRP2 overexpressing cells increased CD206 on macrophages. Together, these findings present SFRP2 as a SOX2-antagonist with the capacity to induce a mesenchymal subtype transition in glioma cells located in vascular tumor areas, highlighting its role in glioblastoma tumor evolution and intratumoral heterogeneity.