Glioblastoma invasion factor ODZ1 is induced by microenvironmental signals through activation of a Stat3-dependent transcriptional pathway

Veronica Vidal,Carlos Velasquez,Ana Talamillo,Jose L Fernandez-Luna,Olga Gutierrez

doi:10.1038/s41598-021-95753-6

Veronica Vidal, Carlos Velasquez + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-95753-6

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Abstract

We have previously shown that the transmembrane protein ODZ1 serves for glioblastoma (GBM) cells to invade the surrounding tissue through activation of RhoA/ROCK pathway. However, the transcriptional machinery used by GBM cells to regulate the expression of ODZ1 is unknown. Here we show that interaction with tumor microenvironment elements, mainly activated monocytes through IL-6 secretion, and the extracellular matrix protein fibronectin, induces the Stat3 transcriptional pathway and upregulates ODZ1 which results in GBM cell migration. This signaling route is abrogated by blocking the IL-6 receptor, inhibiting Jak kinases or knocking down Stat3. Furthermore, we have identified a Stat3 responsive element in the ODZ1 gene promoter, about 1 kb from the transcription start site. Luciferase-reporter assays confirmed that the promoter responds to the presence of monocytic cells and this activation is greatly reduced when the Stat3 site is mutated or following treatment with a neutralizing anti-IL-6 receptor antibody or transfecting GBM cells with a dominant negative variant of Stat3. Overall, we show that monocyte-secreted IL-6 and the extracellular matrix protein fibronectin activate the axis Stat3-ODZ1 and promote migration of GBM cells. This is the first described transcriptional mechanism used by tumor cells to promote the expression of the invasion factor ODZ1.

Highlights

We have previously shown that the transmembrane protein ODZ1 serves for glioblastoma (GBM) cells to invade the surrounding tissue through activation of RhoA/ROCK pathway
We argued that some of these microenvironmental interactions may serve to induce the expression of ODZ1, which facilitates GBM cells to invade the neighboring parenchyma
We showed that fetal calf serum, fibronectin and IL-6 were able to upregulate ODZ1 in GBM cells

Summary

Introduction

We have previously shown that the transmembrane protein ODZ1 serves for glioblastoma (GBM) cells to invade the surrounding tissue through activation of RhoA/ROCK pathway. We show that interaction with tumor microenvironment elements, mainly activated monocytes through IL-6 secretion, and the extracellular matrix protein fibronectin, induces the Stat[3] transcriptional pathway and upregulates ODZ1 which results in GBM cell migration. One of the main signaling mediators in tumor cells is Stat[3], which is involved in driving cell survival, proliferation, invasion and metastasis among other a ctivities[9,10] and this transcription factor is tipically activated by triggering growth factor and cytokine receptors It has been established a gene signature that stratifies GBM patients into Stat3-high and Stat3-low cohorts and showed that inhibition of Stat[3] signaling reduces Stat3-high cell viability and tumorigenicity in vivo[11]. We found an active Stat site in the ODZ1 promoter that responds to both stimuli and showed that mutagenesis of this site or blocking interaction of IL-6 with its cognate receptor abrogates transactivation

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