SOX-BMI1

Figure 1. An extra copy of Ink4/Arf and p53 attenuates NSCs function decline in SVZ with aging (C) Expression of several NSC markers is elevated in SVZ from aged (24-30 months) transgenic mice. (D) Neuroblast and neuronal markers of are also elevated in olfactory bulbs of aged transgenic mice.

Glioma stem cells play a significant role in the initiation, maintenance and development of certain forms of tumour, including glioblastoma multiforme, a highly malignant form of brain cancer. New strategies to directly target these cells could lead to great improvements in treatment, as Dr Ander Matheu of the SOX-BMI1 project explains

cells plays a central role in generating, maintaining and repairing the central nervous system throughout life. However, as we age the number of neural stem cells declines, a process which has been associated with a decline in cognitive activity and neurodegenerative diseases and the emergence of certain mutations, which can have significant consequences for personal health. “Mutations in these cells induce cell transformation, which can lead to tumour formation and glioblastomas,” says Dr Ander Matheu. Based at the Biodonostia health research institute in the Spanish city of San Sebastian, Dr Matheu is the Principal Investigator of the SOX-BMI1 project, an initiative investigating the transformation of neural stem cells and their role in certain pathologies, including glioblastomas and neurodegenerative disease. “We aim to discover whether a general mechanism affects the different pathologies associated with aging,” he outlines.

A key focus in this research is the development of cancer stem cells and the maintenance of their characteristics. Mutations in neural stem cells can lead to their transformation into glioma stem cells, a rare subpopulation of tumour cells, which leads to the development of glioblastoma, a highly aggressive form of brain tumour. “It has been established that specific mutations in neural stem cells induce tumours and glioblastoma, in part by affecting the TP53 protein,” says Dr Matheu. Indeed, results generated within the project and published in the journal Aging Cell demonstrates that mice carrying a combined extra copy of p53 and Ink4/Arf display elongated lifespan, delayed neural stem cell

Established therapies like chemotherapy and radiotherapy are not very effective and the location of the tumour often makes surgery complicated, underlining the importance of continued research. Dr Matheu and his colleagues are investigating the underlying mechanisms and factors behind the maintenance and function of both neural stem cells and glioma stem cells; two specific transcriptor factors – SOX9 and BMI1 – are known to play an important role in these terms. “If

neural stem cells lack SOX9 or BMI1 then they differentiate. They don’t maintain the characteristics of stem cells and they cannot proliferate,” he explains. Researchers in the project are investigating the significance of both SOX9 and BMI1 in regulating the population of cancer stem cells, using both animal models and cell samples from human patients. “We have been able to isolate and generate cultures of human glioma stem cells. We also have

Glioblastomas are very aggressive, and they are resistant to commonly used therapies. The prognosis for patients is poor, as established therapies like chemotherapy and radiotherapy are not very effective, and the location of the tumour often makes surgery complicated

exhaustion and enhanced resistance to cellular transformation and tumor formation (Carrasco-Garcia et al., 2015).

Glioma stem cells are not only involved in the initiation and maintenance of the disease, but also its progression and later resistance to therapy. “Glioblastomas are very aggressive, and they are resistant to commonly used therapies, so the prognosis for patients is poor” continues Dr Matheu.

cultures of neural stem cells, from both mice and humans,” outlines Dr Matheu.

This approach allows Dr Matheu and his colleagues to study both the initial cause of a tumour, and the mechanisms behind its maintenance, progression and recurrence. With the mouse models that are being used in the project, researchers are able to study the initiation of glioblastomas, whereas the tumour is already established in human tissue samples, from which new insights can be drawn into its maintenance and progression. “There we can study the maintenance of a tumour and the factors behind resistance to therapy,” says Dr Matheu. Researchers manipulate the expression of SOX9 and BMI1 in glioma stem cells to try and characterise their role in the regulation of these cells. “We know that high levels of both of these proteins are expressed in the cell lines that we have generated,” continues Dr Matheu. “We modulate their activity through lentiviral infections, and we then characterise what is happening at the cellular level.” Interestingly, we have found that SOX9 genetic inhibition significantly impairs the activity and malignant features of glioma stem cells. This work has been recently published in Expert Opinion On Therapeutic Targets journal (Garros-Regulez et al., 2016).

Researchers are studying cell differentiation and tumour activity, aiming to build a fuller picture of the role of SOX9 and BMI1 in the development and maintenance of cancer, work which could

Expression of SOX9 in GBM and gastric cancer biopsies eventually yield important therapeutic insights. One area of particular interest to Dr Matheu and his colleagues is the role of SOX9 in resistance to therapy. “We have found that the activity of SOX9 is responsible for resistance to Temozolomide, the form of chemotherapy most commonly used in the clinic,” he says. Researchers are working to identify drugs that inhibit the activity of SOX9, and significant advances have been achieved. “We have found that Rapamycin inhibits the general function of glioma stem cells through the inhibition of SOX2 and SOX9. Rapamycin is an agent that inhibits mTOR activity, one of the main activated pathways in glioblastoma,” explains Dr Matheu. “The effects of Rapamycin are extensive, so we aim to find a drug to directly inhibit these glioma stem cells.”

This holds important implications for cancer therapy. Evidence suggests that targeting SOX9 or BMI1 could block the characteristics of cancer stem cells, which could represent a new avenue for treating not only glioblastoma but also additional types of cancers such as colorectal and gastric cancers where the group of Dr. Matheu identified that SOX9-BMI1 axis plays a relevant role in the maintenance of cancer stem cells. These works have been recently

Role of SOX9-BMI1 in adult neural stem cells and in glioma stem cells (SOX-BMI1)

The goals of this translational research project are to investigate the clinical relevance of SOX9-BMI1 in glioblastoma, to characterize its role in the regulation of glioma stem cells and to determine whether Sox9-Bmi1 concomitant overexpression is sufficient to induce neural stem cell transformation and cause gliomas. To achieve our aims, we will generate a unique set of cellular and animal models to study in vitro and in vivo the biology of neural and glioma stem cells.

Funding provided by Marie Curie Career Integration Grant CIG 712404.

• Nicolas Sampron (Donostia Hospital) • Robin Lovell-Badge (The CRICK Institute)

Head of Neuro-Oncology Group Leader, Biodonostia HRI Pº Dr. Beguiristain s/n 20014 Donostia – San Sebastián Gipuzkoa T: +34 943 00 6073 E: ander.matheu@biodonostia.org W: www.biodonostia.org/en

Dr Ander Matheu

High levels of SOX9 in glioma stem cells correlate with tumor progression

published in Scientific Reports (CarrascoGarcia et al., 2016) and Cancer Research (Santos JC et al., 2016) journals. Dr Matheu and his colleagues plan to investigate this therapeutic potential further. “We also aim to identify small molecules that can inhibit this protein and try to translate that to the clinic,” he says. This of course is central to therapeutic development, and while translating laboratory research into clinical Both SOX9 and BMI1 are commonly overexpressed in several forms of cancer, which Dr Matheu says was an important part of the original motivation behind the project. “We’ve postulated that inhibition of this pathway would help not only reduce or eliminate brain tumours and glioblastoma, but also other types of tumours. There is clear evidence that this will be a good therapeutic strategy in other

types of cancer, including colo-rectal, breast, and gastric cancer,” he outlines. Since SOX9 and BMI1 are involved in regulating stem cells and a decline in stem cell activity occurs with aging, this opens up further avenues of investigation. “We are also planning to study the impact of SOX9 and BMI1 on aging associated disorders such as neurodegenerative diseases,” continues Dr Matheu.

developments can be a complex process, Dr Matheu is keen to investigate potential anticancer therapies. “We are trying to directly target cancer stem cells. The preliminary data from the project suggests that this is possible,” he says.

The project’s research also holds wider relevance beyond the specific example of glioblastoma to encompass other forms of cancer and neurodegenerative disease.

Dr Ander Matheu’s main research interests are cancer and the process of ageing. He gained his Ph.D. under the supervision of Dr. Manuel Serrano, and he currently prioritises translational research, in order to ensure that basic discoveries have practical applications and help to improve human health.