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Method developed to identify treatment resistant cancer cells in tumours

Researchers have developed a novel way to understand tumour heterogeneity that could be used to prevent cancer relapse. The study, published in eLife, described the development of a transcriptomics and sequencing-based technique that can track and kill treatment-evading cancer cells in breast cancer mouse models.

Tumour heterogeneity underpins treatment resistance

Cancer arises when cells gain genetic mutations that drive uncontrolled growth. This results in the formation of a tumour, which is made up of a mass of cancer cells that can have slightly different genetic compositions. As a result, the drug susceptibility of cells within a tumour can differ. Some cells will be susceptible to the anti-cancer drugs and die whereas other cells will be resistant. The treatment resistant cells can regrow to form the tumour and lead to relapse. Differentiating the cell types that are responsible for resistance and relapse within tumours has been challenging.

The IMAXT lab at the Cancer Research UK Cambridge Institute used mouse tumours to develop a method for identifying treatment resistant cancer cells within tumours.

Dr Kirsty Sawicka, Postdoctoral Research Associate at the Cancer Research UK Cambridge Institute said, “Tumours are incredibly complex, made up of many different types of tumour cells that have acquired genetic mutations as they evolve and replicate – and some of these cells are able to evade standard cancer treatments. Until now, it hasn’t been possible to work out which these cells are and what makes them special, but our technique means that we can now do just that.”

A WILD method

The researchers used clonal transcriptomics with WILD-seq (Wholistic Interrogation of Lineage Dynamics by sequencing), which is a genetic barcoding system (figure 1). Viruses with WILD-seq barcodes were used to genetically tag different types of breast cancer cells. Barcoded clones were selected using FACS, stabilised in culture and injected into mice to form ’trackable’ tumours in a mouse model of breast cancer.

Figure 1: Schematic WILD-seq pipeline. WILD-seq barcoded viruses were generated and used to form breast cancer tumours in mice. Source: Published in eLife.

The researchers then treated the breast cancer using the same drugs (BET bromodomain inhibition and taxane-based chemotherapy) that are used on patients. They then scanned the barcodes and used single-cell sequencing technology to identify the different types of cancer cells. They identified the cells that were treatment-resistant.

The researchers identified that the evading cells used the amino acid asparagine. They used an enzyme-based chemotherapy drug called L-asparaginase, which is usually used to treat patients with acute lymphoblastic leukaemia, to break down the amino acid. This allowed them to specifically target and kill these treatment-resistant cancer cells. 

Dr Ian Cannell, Cancer Biologist in the IMAXT lab at the Cancer Research UK Cambridge Institute said, “Offering some kind of ‘combination therapy’ that adds asparaginase to the standard treatment could be a way of further shrinking tumours in breast cancer patients and reducing their risk of relapse.”

Future applications

Standard treatments may fail because not all cells within a tumour are the same. The study details a transcriptomic and sequencing-based method that identifies chemotherapy-resistant mechanisms in cancer cells that are druggable. It highlights a targeted therapeutic approach to preventing breast cancer relapse in patients by identifying which types of cancer cells die and which survive. However, the technique was developed using mouse tumours so further studies are required to develop a method that could be used in humans.

 Dr Ian Cannell said, “Although we see evidence that these evasive tumour cells are increased in patients after chemotherapy, so far, we’ve only shown that we can target them in mice, so there’s still a long way to go before it leads to a treatment for patients.”