PERSIST-SEQ leverages AstraZeneca’s expertise in cancer models and single cell sequencing

Importantly, AstraZeneca has access to a range of biological models (cell lines, organoids, PDX) that represent the main cancer types proposed for investigation in PERSIST-SEQ, and has experience in the acquisition of single cells from such models. In addition, they have a dedicated bioinformatics team with experience in the analysis of single cell sequencing data and will be working with Single Cell Discoveries (Work Package 7) to develop new analyses methods for the consortium.

Ultan McDermott - Chief Scientist in Early Oncology, Oncology R&D at AstraZeneca and a clinician scientist, and Viia Valge-Archer - Senior Director, External R&D Scientific and Clinical Alliances, Oncology R&D at AstraZeneca, elaborate further on AstraZeneca’s role in PERSIST-SEQ in the duo-interview below.

What is the unique contribution of AstraZeneca to the PERSIST-SEQ project?

As a leading biopharmaceutical company in the development of new therapies for cancer patients, AstraZeneca has deep expertise in both cancer biology and drug resistance, as well as in the identification of new drug targets. Single-cell sequencing data from drug-resistant cancer cells is ‘big data’ – large and complex, and application of insights from AstraZeneca’s experience in cancer therapeutics (together with that of all the other PERSIST-SEQ partners) will be crucial in integrating and translating our increased understanding of the biology of cancer persister cells into tomorrow’s potential new cancer treatments.

What technologies are used in PERSIST-SEQ and how will they help explain therapy resistance in cancer?

Drug resistance is one of the main challenges in cancer treatment.. So far efforts in overcoming resistance have focused on genetic (i.e. DNA based) causes when patients relapse or cancer treatment stops working. However,  there is an increasing interest in understanding why some cancer cells do not die (‘persister’ cells) at a much earlier stage of treatment. Evidence points to a number of non-genetic mechanisms that drive this persistence. Single-cell sequencing has quickly become the ‘go to’ technology to analyse these rare cells. In PERSIST-SEQ, single-cell RNA sequencing is the default technology to investigate persister cells.  Depending on the biological question, we can also apply other single cell technologies to address epigenetic changes and to capture the spatial distribution of transcriptomic changes. Single-cell sequencing is a fast-moving field and it is important that PERSIST-SEQ takes advantage of all the new cutting edge technologies as they emerge.

What is the most challenging aspect of the PERSIST-SEQ goals, in your opinion?

Having a consortium of 14 European partners from industry and academia, means we have a wide range of objectives, expectations and cultural differences. Our challenges are mainly technical, logistical and organisational.

On the technical side, single-cell sequencing is one of the most important new technologies developed in the past decade, in  a complex and fast-moving field.. Over the first five years of PERSIST-SEQ, it’s critical that we continue to pioneer in single cell sequencing, and establish effective ways of working.  

The logistics of preparing single cells in a range of different laboratories and shipping to the sequencing company in the Netherlands has been challenging. We are continually learning and improving our approaches.   

Lastly, managing the consortium operations  brings with it  a set of challenges. To address these and bring the different partners together, Lygature acts as a neutral partner and advises on regulatory and IP issues, and maintains effective dissemination of information and communications. 

What is your general opinion on such a large collaboration between industry partners, government, and academia?

As science becomes more technically challenging and data analysis - more complex, it is increasingly difficult for any one organisation to have access to all the different skill sets required to do ‘big science’. The most impactful science today is the result of collaborations between organisations and across disciplines to pool the required expertise. Additionally, bringing together academia, industry and government helps ensure that impactful discoveries in human health have the best chance of being translated into the clinic.

What is the importance of the project for the wider field of cancer research?

Drug resistance to treatment continues to be an unfortunate challenge  for many cancers. With some exceptions, it is the cause of most cancer deaths in patients diagnosed with metastatic disease.  For this reason, improving our understanding of  mechanisms of resistance continues to be a major area of focus. Tumour plasticity works against current therapies  and gives rise to therapeutic resistance, and has been explored from many different angles in recent decades. However, there is still no comprehensive understanding of the underlying resistance mechanisms, nor how they differ between cancer types or therapies.

Defining rational drug combinations to overcome resistance is extremely challenging and has prompted many groups to begin to analyse cancer cells at a much earlier stage of the transition to drug resistance,  with a focus on  persistent or residual cancer cells after initial treatment. Drug tolerant persister cells exploit non-genetic, (transcriptional pathways,  avoid cell death and lead to the stable genetic resistance we observe in relapsing patients.  A variety of different mechanisms of cancer cell persistence have been proposed, ranging from effects of cell cycle, tumour microenvironment interactions, adaptations of cell metabolism and changes in cell state.