Researchers at the Cancer Research UK Cambridge Institute at the University of Cambridge report that they have developed a new technique for identifying the different types of cells in a tumor. Developed in mice, the method allows them to track the cells during treatment, seeing which types of cells die and which survive. The scientists, who believe the approach is a step towards the development of new treatments to prevent relapse in patients, published their study “Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies” in eLife.

“Tumor heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilize clonal transcriptomics with WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, in mouse models of triple-negative breast cancer (TNBC) to understand response and resistance to therapy, including BET bromodomain inhibition and taxane-based chemotherapy,” write the investigators.

“These analyses revealed oxidative stress protection by NRF2 as a major mechanism of taxane resistance and led to the discovery that our tumor models are collaterally sensitive to asparagine deprivation therapy using the clinical stage drug L-asparaginase after frontline treatment with docetaxel.

“In summary, clonal transcriptomics with WILD-seq identifies mechanisms of resistance to chemotherapy that are also operative in patients and pinpoints asparagine bioavailability as a druggable vulnerability of taxane-resistant lineages.”

Tumors are complex

According to Kirsty Sawicka, PhD, from the Cancer Research UK Cambridge Institute said: “Tumors are incredibly complex, made up of many different types of tumor cells that have acquired genetic mutations as they evolve and replicate. 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.”

The team, based in the IMAXT lab of Greg Hannon, PhD, used viruses to tag different types of breast cancer cells with a unique genetic barcode. They then formed tumors from these cells in mice and treated them with the same drugs used to treat patients with breast cancer.

By scanning the barcodes using recently developed single cell sequencing technologies, which look for those genes that are turned on or off in the cell, they were able to identify the different types of cancer cells, how many of those cells there are and what their characteristics are, and which types of cancer cells are not killed effectively by standard treatments.

The team noticed that the cells that evade chemotherapy are those that have a greater reliance on asparagine, an amino acid that cells use to protect themselves from damage. By then administering L-asparaginase, a drug currently used to treat patients with acute lymphoblastic leukemia, they were able to specifically target and kill these tumor cells.

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

“Although we see evidence that these evasive tumor 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. Before we can do that, we need to find the best way of administering the drugs. Would we give the drugs together, for example, or offer the standard treatment and then asparaginase.”

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