Thursday, April 08, 2021

Related To Montagnier's Concern About mRNA? Extrachromosomal DNA Drives Tumor Malignancy

thescientist |   Despite being treated with drugs designed to target this gene, the patients were not getting better, and when we interrogated the genomes of their cancers after the tumors were surgically removed following treatment, we saw that they had changed. The tumors had dramatically reduced the number of copies of the targeted epidermal growth factor receptor (EGFR) gene, presumably giving them an advantage to escape the drugs, and they had evolved these genetic differences at a rate that seemed to make no sense—within just one to two weeks. 

Normally, we think of cancers evolving over many cell divisions, as the cells carrying genetic changes that provide a fitness advantage—such as an ability to resist a particular treatment—will be more likely to survive and divide. Here, we were noticing a change in the copy number of the gene within just a few generations. There was no way that we could explain how the tumors were altering their DNA so quickly. 

Even stranger, we could take any cell from the tumor, and whether it had high or undetectable protein levels of EGFR, it would give rise to a new tumor when cultured in the lab or implanted into a mouse. Each of these new tumors would then display the full spectrum of cells found in the original tumor, varied in their EGFR copy number. This makes no sense according to what we know about classical genetics. We would have expected that tumors arising from a cell with low levels of EGFR would give rise to a tumor with low EGFR levels, whereas a tumor arising from a cell with high levels of EGFR would give rise to a tumor with high EGFR levels. 

When we removed the treatment with the EGFR inhibitor from cultured tumor cells, EGFR copy number quickly rebounded, but again, not on chromosomes. When we saw this, we realized that ecDNA might explain why some cancers can become resistant to treatment so quickly, allowing tumors to evolve at a rate that far exceeds anything that could be accounted for by classical genetics. We published our results in Science in 2014, but they were not immediately accepted by the community. Although we had only studied one tumor type, glioblastoma, we began to wonder whether this might be the tip of the iceberg. 

Without realizing it, this study led us, and now others, to a series of discoveries that have changed the way that researchers view cancer in general, revealing frightening ways that tumors can evolve. We have learned that ecDNA is central to the behavior of some of the most aggressive forms of cancer, enabling remarkably elevated levels of oncogene transcription, creating new gene regulatory interactions, and providing a powerful mechanism for rapid change that can drive very high oncogene copy numbers or allow cancer cells to resist treatment. Fist tap Woodensplinter