Skip to content
Dr Florian Siebzehnrubl

Dr Florian Siebzehnrubl

Research Fellow, European Cancer Stem Cell Research Institute, School of  Biosciences

School of Biosciences

Email:
fas@cardiff.ac.uk
Telephone:
+44 (0)29 2068 8500
Location:
Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ
Available for postgraduate supervision

Research overview

Stem cells exhibit remarkable abilities to maintain their identity and to generate cells of different lineages. In normal tissues, they are responsible for replacement of cells lost through wear and tear, and for tissue repair after injury. In cancer, neoplastic stem-like cells apparently have a greater capacity for initiating tumour growth and are frequently resistant to anti-cancer treatments.

My lab focuses on understanding the molecular regulators of normal and cancerous stem cells in the CNS. We use in vitroand in vivoapproaches to address how neural stem cells maintain their identity in the brain, and how cancer stem cells contribute to malignancy and tumour progression in glioblastoma, the most common and most lethal brain cancer in adults.

2019

2018

2017

2015

2014

2013

2012

2011

2010

2009

2008

2007

2006

2005

Summary

My lab investigates how stemness and cell differentiation are regulated in brain cancer and CNS homeostasis.

Brain Cancer Stem Cells

Brain cancers, especially glioblastoma, continue to carry an exceedingly poor prognosis despite several decades of research directed at improving our understanding and management of these diseases.  The cancer stem cell hypothesis has helped to shift the scientific focus towards the study of specific tumour cell types, but the actual functions of individual cancer cell subpopulations within a single tumour are poorly understood. However, it is becoming increasingly clear that some cancer cells are more capable of inducing tumour growth and more resistant to conventional therapies. We call these cancer stem cells. Whether cancer stem cells are the source of functionally discreet tumour cell subpopulations remains unknown. 

Stem-cell Transcription Factors

My research focuses on regulatory mechanisms that govern essential processes of malignancy in glioblastoma cancer stem cells (GSCs), such as tissue invasion, therapy resistance and the initiation of tumour growth. The transcription factor ZEB1 (zinc finger E-box binding homeobox 1) is able to regulate all of these processes in GSCs (Siebzehnrubl et al. 2013; Hoang-Minh et al. 2018) through an intricate pattern of regulatory steps involving microRNAs and downstream transcription factors and effector genes. ZEB1 is part of an auto-regulatory loop together with SOX2 and OLIG2, two additional stem cell transcription factors, that can drive tumour growth in glioblastoma. My lab investigates whether the transcription factor ZEB1 is a molecular regulator of cell state transition in GSCs.

Functions of ZEB1 in GSCs

In addition to their greater potential for initiating tumour growth and recurrence, GSCs are highly invasive and resistant to chemo- and radiotherapy. We have found that higher expression of ZEB1 in GSCs compared to non-stem glioblastoma cells causes increased expression of the chemoresistance enzyme, MGMT. ZEB1 further promotes GSC invasion through upregulation of the axon guidance molecule, ROBO1 (Fig. 1). Therefore, ZEB1 is a key regulator of multiple pro-malignant processes in GSCs.

Environmental regulators of ZEB1

The protein structure of transcription factors is usually very flexible, as these proteins interact with a number of potential binding partners and DNA to exert their regulatory functions. Because of this, transcription factors lack classical binding pockets that are present in many enzymes and present challenging targets for pharmacological inhibition.

We are therefore identifying upstream regulators of ZEB1 expression that are present in the tumour microenvironment and that may present better opportunities for pharmacological targeting.

Functions of ZEB1 in the normal brain

ZEB1 is known as a transcriptional regulator in cancer stem cells, while its functions in normal tissues are less understood. Constitutive knockout of ZEB1 is lethal around birth, therefore studies on the functions of ZEB1 in the CNS have thus far been limited to embryonic development.

We are currently investigating the functions of ZEB1 in astrocytes, and in homeostasis of the adult brain using new conditionally inducible transgenic models.

 

Current grant support

As lead applicant

MRC “Defining the roles of FGF receptors on glioblastoma stem-like and non-stem cell populations” (2019 – 2022, FEC £795k)

Innovate UK KTP project “Investigating biodistribution of therapeutic exosomes” (2019 – 2021, FEC £158k)

Tenovus Cancer Care “Functions of MIF in glioblastoma progression” (2015-2019, £105k)

As co-applicant

NC3Rs “Development of human glioma OrganDots” (2016-2019, £90k)

MRC GW4 DTP “Targeting the Ubiquitin-proteasome system in glioblastoma” (2018-2021, £77k)

KESS Studentship “Narciclasine, an accessible natural product as lead compound for the treatment of gliomas” (2017-2020, £66k)

 

External collaborators

Karin Forsberg-Nilsson (Uppsala University, Sweden)

Justin D. Lathia (Cleveland Clinic, USA)

Thomas Brabletz (University Erlangen-Nuremberg, Germany)

Geert Berx (VIB Ghent, Belgium)

 

Affiliated Staff

Postgraduate Research Students

  • Brain cancer
  • Adult neurogenesis
  • Neural Stem Cells