Amazing stuff! Cancer is history (soon)!
"... Normal human cells generally keep their DNA in chromosomes. But that’s hardly the only way ecDNA disregards norms. Research ... delineates how it violates one of the fundamental principles that govern inheritance to aid tumors’ growth and make them more resilient. Together with international collaborators, they show the scope of ecDNA’s contribution to cancer, especially to the most pernicious cases. ...
That perception began to change roughly a decade ago, when ... team traced the numerous copies of cancer-driving genes, or oncogenes, often found in tumors to ecDNA – not chromosomes, where they were assumed to reside. ...
This, the researchers have determined, is central to how ecDNA molecules contribute to cancer: Their DNA is transcribed — or turned into mRNA, an early step in gene expression — four times more than the same sequences on chromosomes. ...
Under the normal rules of inheritance, this toxic synergy shouldn’t persist. Yet it does. New research ... shows how. ... "
found that ecDNAs come together to form hubs. While in close proximity, distinct ecDNA molecules interact, with expression-enhancing elements on one elevating the activity of oncogenes on separate ecDNAs.
From the abstract:
"The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division. Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells. How multiple ecDNA species within a tumour cell are assorted and maintained across somatic cell generations is unclear. Here we show that cooperative ecDNA species are coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. ecDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy-number gains in multiple ecDNA species before any selection. Intermolecular proximity and active transcription at the start of mitosis facilitate the coordinated segregation of ecDNA species, and transcription inhibition reduces co-segregation. Computational modelling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations."
Fig. 1: ecDNA species encoding distinct oncogene sequences are correlated in individual cancer cells.
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