Steve Pollard Research Group

Our research team is tackling one of the most challenging human cancers — the aggressive brain cancer glioblastoma. This is an area of huge unmet need as survival rates are poor (Aldape et al. 2019). 

We combine deep insights into the fundamental biology of cancer with cutting-edge innovation to create next-generation therapies. To drive discovery, we’ve built an arsenal of advanced experimental models — spanning both mouse and human systems — that are now used worldwide by leading scientists and industry partners. These powerful tools are revealing fresh, high-impact drug targets and accelerating the development of first-in-class therapeutics with the potential to transform patient outcomes.

Professor Steven Pollard

Associate Director, Cancer Research UK Scotland Centre; Director, Brain Cancer Centre of Excellence

• Centre for Regenerative Medicine
• Institue for Regeneration & Repair and Cancer Research UK Scotland Centre
• BTR Scottish Brain Cancer Centre of Excellence

Contact details

• Website: Personal Profile
• Work: 0131 651 9500
• Email: steven.pollard@ed.ac.uk

Research interests

Many human cancers hijack the molecular programs normally reserved for immature stem cells, using them to maintain relentless self-renewal and evade terminal differentiation. In tumours, these pathways run unchecked — making them prime targets for new therapies. Our research focusses on the biochemical and cellular mechanisms regulated by a group of master regulatory transcription factors — the “command switches” that lock cells into an immature cancer stem cell state. By decoding how these powerful gene regulators work, we aim to expose vulnerabilities that can be exploited for transformative treatments.

We are driven by three overarching research questions:

We are developing innovative strategies to dismantle this cancer stem cell-like identity. Many of the pivotal regulators we and others have identified over the past decade are neurodevelopmental transcription factors — including members of the SOX, FOX, HOX, and bHLH families (Bulstrode et al.). These factors, often redundant and notoriously difficult to “drug” with standard medicinal chemistry, underpin the plasticity that defines both normal stem cells and cancer stem cells.

Our lab’s research combines patient-derived models (Pollard et al.), CRISPR genome editing (Bressan et al., and Dewari et al.), synthetic biology, genomics, immunotherapy, and AAV-based gene therapy. Although our primary focus is the lethal brain cancer glioblastoma, our approaches have clear potential across multiple tumour types. Through collaborations with academic and industry partners, we are now extending our work to colorectal, lung, and liver cancers.

The five ongoing projects described below build on our past discoveries, leverage our unique experimental models, and draw on direct access to primary patient samples through strong clinical partnerships in Edinburgh.

Key projects

Experimental models and tools to tackle glioblastoma

(reviewed in Robertson et al., 2019)

• Building on our original discoveries we have developed The Glioma Cellular Genetics Resource (GCGR). This is a suite of deeply characterised patient-derived GBM stem cell lines, normal (non-transformed) neural stem cells (NSC) lines, engineered derivatives and reporters, and a wealth of associated molecular profiling data. (Morrison et al., in preparation)
• A CRISPR toolkit that enabled us to build up the glioma driver mutations stepwise and in combinations, as well as routinely knock-in biochemical tags or reporters to track protein targets.
• Immune evasion mouse models that confirmed functional the importance of transcriptional and epigenetic plasticity in driving immune evasion via resetting of the tumour microenvironment.
• These programs were supported by Cancer Research UK Senior Fellowship and Centre Accelerator Awards and underpin all research projects in our lab.
• Ongoing projects include development of more complex co-culture models, particularly immune-tumour interactions in both 2D and 3D.

Identification of the core biological vulnerabilities of glioblastoma

(Reviewed in Williams et al, 2019)

• SOX, FOX and bHLH proteins have emerged as key regulators that sustain the immature cancer stem cell identity and restrict differentiation.
• Quiescence control has been underexplored, but is a key mechanism through which the GBM stem cells can evade current therapeutic approaches and drive relapse.
• Terminal differentiation programs that restrict the hallmarks of cancer pathways are dysfunctional in GBM stem cells, limiting current differentiation therapy approaches
• We are exploring the mitotic bookmarking and pioneer activity of key factors, such as SOX2, revealing important new molecular processes that underpin reestablishment of the GBM stem cell regulatory networks at each cell division.

Key collaborators: Abdenour Soufi (pioneer transcription factors and reprogramming). Supported by a Cancer Research UK Program Grant.

Phenotypic screening and small molecules for targeting glioblastoma

(Reviewed in O’Duibhir et al., 2017)

• Using novel reporter cell lines to track GBM stem cell identity, we have been screening large libraries of small drug-like molecules to uncover those which can target the GBM stem cells with limited effects on normal NSCs.
• A series of lead candidates has emerged that are being validated and moving into drug development programs.

Key collaborators: Prof Asier Unciti-Broceta in medicinal chemistry and Prof Neil Carragher (phenotypic screening), within the Brain Tumour Research Scottish Centre of Excellence.

Engineering biology mission hub:  gene therapy payloads for cancer

• Building on the previous UK Mammalian Synthetic Biology Centre discoveries, we are currently exploring a set of innovative genetic payloads and combinations to target cancer stem cells.
• We have also developed a set of novel AAV capsid engineering approaches.

Key collaborators: Prof Susan Rosser (Engineering Biology Mission Hub) & Prof Andy Baker (MRC BHF/CoRE) working on genetic control technologies.

Viral immunotherapy for GBM

(Reviewed in, Swift et al., 2022)

• We have developed a new approach to create synthetic super-enhancers (SSEs). These are engineered regulatory elements that enable strong, but highly cancer-selective, expression of genetic payloads within the GBM stem cells. This enables us to deliver combinations of cytotoxic and immune activating payloads with precision, i.e. we can hit the cancer cells hard and early (Koeber and Matjusaitis, under review).
• Using the SSE controlled payloads, and delivery via an adeno-associated viral vector, we have built a first-in-class gene therapy. This has demonstrated remarkable efficacy in laboratory models.
• The SSE technology and lead candidate for GBM is now being moved into clinical testing, led by Trogenix Ltd., a new University of Edinburgh spin-out company (www.trogenix.com).
• Ongoing projects are continuing to explore the utility of SSEs as cell state reporters across diverse contexts in development, regeneration and cancer.

Key collaborators: Trogenix Ltd & Prof Paul Brennan and Dr Faye Robertson (NHS Lothian).

Key publications

1. Robertson, F. L. et al. Elevated FOXG1 in glioblastoma stem cells cooperates with Wnt/β-catenin to induce exit from quiescence. Cell Rep. 42, 112561 (2023).
2. Swift, E. A., Pollard, S. M. & Parker, A. L. Engineering cancer selective virotherapies: are the pieces of the puzzle falling into place? Hum Gene Ther 0, (2022).
3. Gangoso, E. et al. Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion. Cell 184, 2454-2470.e26 (2021).
4. Marqués-Torrejón, M. Á. et al. LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells. Nat Commun 12, 2594 (2021).
5. Bressan, R. B. et al. Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants. Cell Stem Cell 28, 877-893.e9 (2021).
6. Bulstrode, H. et al. Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators. Gene Dev 31, 757–773 (2017).
7. Carén, H. et al. Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest. Stem Cell Rep 5, 829–842 (2015).
8. Stricker, S. H. et al. Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Gene Dev 27, 654–669 (2013).
9. Pollard, S. M. et al. Glioma Stem Cell Lines Expanded in Adherent Culture Have Tumor-Specific Phenotypes and Are Suitable for Chemical and Genetic Screens. Cell Stem Cell 4, 568–580 (2009).

Biography

Steve Pollard is Professor of Stem Cell and Cancer Biology at the University of Edinburgh. He trained in developmental genetics at NIMR (now the Francis Crick Institute) and studied stem cell gene regulation as a postdoc with Prof Austin Smith at Cambridge. As a Wellcome Beit Fellow and Cancer Research UK Senior Fellow, he uncovered how brain cancers hijack neural stem cell programs. His group has also generated a suite of improved methods, tools and cell lines that have been widely shared with the community. His lab has used these to uncover novel biological processes driving brain tumours, identified new therapeutic targets, and development of first-in-class innovative gene therapy strategies that are moving into clinical testing.

Steve leads the CRUK Brain Cancer Centre of Excellence, is Associate Director of the CRUK Scotland Centre, and part of the leadership team for the Edinburgh-led UKRI Engineering Biology Mission Hub. In 2023, he founded Trogenix Ltd, a spinout biotech spinout applying cancer models, synthetic biology, gene therapy, and immuno-oncology to develop precision genetic medicines for cancer.

Trogenix Ltd

Group Members

Neza Alfazema, Research Technician

Serena Barilla, Research Fellow

Michelle Clark, Research Fellow 

Vivien Grant, Laboratory Manager

Hei Ip Hong, Martin Lee Doctoral Scholarship Student

Carla Jacinto, Laboratory Manager

Isabella Jamieson Morris, PhD Student

Erika Lo, PhD Student

Heather MacPherson, Research Assistant

Gillian Morrison, Research Manager

Shahida Sheraz, Research Assistant

Zeyu Wang, PhD Student

Rachel White, Laboratory Manager

Charles Williams, Postdoctoral Research Associate

Rosie Willis, PhD Student

Xinying Yeo, Research Fellow

Media engagement

Glioblastoma, immunotherapy and transformative tech - Cancer Research UK (video)

Scientist brings cure for brain cancer to an embryonic stage - The Times (article)

Collaborators

University of Edinburgh collaborators

• Abdenour Soufi (IRR)
• Ahsan Akram (IRR)
• Andrew Wood (IGC)
• Asier Unciti-Broceta (IGC)
• Dirk Sieger (CCDS)
• Faye Robertson (NHS Lothian)
• Ian Chambers (IRR)
• Kevin Myant (IGC)
• Margaret Frame (IGC)
• Neil Carragher (IGC)
• Paul Brennan (CCBS)
• Sarah Walmsley (IRR)
• Susan Rosser (SBS/Engineering)
• Wendy Bickmore (IGC)

External collaborators

• Bill Weiss (UCSF)
• Owen Sansom (CRUK Scotland Institute)
• Peter Dirks (Sick Kids, Toronto)
• Kristian Helin (ICR, London)
• Sergio Quezada (UCL)
• Simona Parrinello (UCL)
• Tom Bird (CRUK Scotland Institute)
• Valerie Weaver (UCSF)

Funders

Cancer Research UK

MRC/BBSRC (UKRI)

Brain Tumour Research

Medical Research Scotland

Trogenix Ltd