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Revealing the genetic diversity of drug-resistant cancer cells

In a recent  Nature paper, researchers have developed a new methodology to track the fates of cancer cells after therapy. By analysing the genetic makeup of cancer cell populations, scientists hope to gain insights into how some cells develop resistance to drug treatments. 

Revealing the future 

The emergence of drug-resistant cells is a major problem in cancer treatment. Anti-cancer drugs efficiently kill many cells in the body, leaving behind a small number of resistant cancer cells to survive. These resistant cells divide, leading to the growth of drug-resistant colonies. However, little is known about the differences in the genetic makeup of resistant cancer colonies. 

To combat this issue scientists developed FateMap, a new method to follow the fates of individual cancer cells as they gain drug resistance. This framework allows characterisation of resistant colonies which develop after treatment with the anti-cancer drug, vemurafenib.

FateMap works by introducing unique barcodes into the genome of BRAFV600E melanoma cell cultures originating from a single cell. After drug treatment, scientists can determine which individual cells belong to which resistant colony using their barcode. Lastly, the translational variation present between different resistant colonies is detected using single-cell RNA sequencing (scRNA-seq). 

The emergence of new resistance types 

Using FateMap, researchers discovered an impressive level of variability between resistant colonies. These differences allowed cells to be grouped into different resistance types, which vary in growth rate, shape, and tissue invasion ability. Resistance types were also linked to changes in the expression of certain genes, with similar results being discovered when FateMap was applied to other cancer types – including a triple negative breast cancer cell line, DA-MB-231-D4. 

Building on this work, the authors investigated whether these differences were present in cancer cells before therapy, or whether genetic changes are caused by a stress response occurring after drug-treatment. Scientists conducted a FateMap “twin study” where pre-treatment cells were barcoded, split into two groups, and the drug applied. Analysis of the resistant colonies which arose from both cultures showed that cells with the same barcode (originating from the same cell pre-treatment) developed the same resistance type. Therefore, the resistance potential of cancer cells appears to be an innate feature present within their genome. 

Changing their destiny 

Following this, researchers then illustrated that the fates of cancer cells can be changed. Altering the drug concentration caused resistance type switching, providing evidence that external factors also influence drug resistance.  

The authors conclude that molecular differences in cancer cells leads to varying resistance outcomes after treatment. However, how the resistance type of cancer cells is determined is still yet to be uncovered.