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

Min Guo,Kaveh M. Goudarzi,Xing-Mei Zhang,Melanie Pieber,Robert A. Harris,Daniel Hägerstrand,Jiri Bartek,Shiva Abedi,Elin Sjöberg,Jinan Behnan,Mikael S. Lindström,Monica Nistér

doi:10.1038/s41388-021-01825-2

Abstract

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 SOX2-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.

Highlights

In this study SOX2 was initially identified as an inducer of glioblastoma subtype transition in an experimental overexpression-screen, and subsequently SOX2 was found through a connectivity map (CMap) analysis to be at the apex of gene expression determination in glioblastoma cultures [31, 32]
SOX2 is expressed in neurogenic regions in human brain including the subventricular zone and in glioblastoma SOX2 is essential for maintaining a tumor- and sphere forming cell phenotype [17, 34]
We find in this study that both SOX2 and POU3F2 appear subordinate to both SFRP2 and KLF4

Summary

Introduction

The intratumoral glioblastoma heterogeneity is well reported in multiple instances [1, 4,5,6,7] and genetically different cell populations have been shown to co-evolve and to be inter-clonally dependent [8]. This is considered to be a major hurdle for successful treatment of glioblastoma, where cells may display differential drug sensitivities, thereby posing an increased risk for developing treatment resistance and the pre-existence of resistant subpopulations, as exemplified in attempts of anti-EGFR treatment and in temozolomide resistance [9,10,11]. The transitions between glioblastoma gene expression subtypes and the spatial organization of different subtype cells in the tumor needs to be further studied for fundamental biological understanding and development of effective treatment against this devastating disease

Methods

Results

Conclusion