Non-genetic determinants of malignant clonal fitness at single-cell resolution
Fennell KA, Vassiliadis D, Lam EYN, Martelotto LG, Balic JJ, Hollizeck S, Weber TS, Semple T, Wang Q, Miles DC, MacPherson L, Chan YC, Guirguis AA, Kats LM, Wong ES, Dawson SJ, Naik SH, Dawson MA. Non-genetic determinants of malignant clonal fitness at single-cell resolution. Nature. 2022 Jan;601(7891):125-131. doi: 10.1038/s41586-021-04206-7. Epub 2021 Dec 8. PMID: 34880496.
Cancer cell evolution has been considered a genetically driven process where a cell acquires an advantageous mutation that allows it to better proliferate or evade therapeutics. Alternatively cells can also have non-genetic, but heritable, mechanisms of evolution that give it a selection advantage.
This paper uses AML as a model to study evolution since it only has one mutation that is necessary and sufficient to cause tumor formation allowing them to easily study non-genetic evolutionary forces. They individually barcoded cells to track them and transplanted them into mice. They found that AML stem cells and more mature progenitor cells were both causing disease with similar proliferation rates. The clonal differences were not a result of the cell of origin. While this demonstrated the non-genetic component, they also saw that descendants of the same barcoded cell became dominant in different mice, showing that the trait was heritable, if unstable.
They then examined the role of Kras and Flt3 oncogene mutations that occur in clonal populations. The dominant clones had a higher expression of Slpi, a gene for an anti-inflammatory protein and a downregulation of immune-related genes like MHC components.
These properties may be made heritable through DNA methylation that silences tumor suppressor genes. scATAC-seq showed reduced chromatin accessibility for B2m which is part of the MHC ssytem. There are also key transcription factors that allow the treatment resistant phenotypes to stabilize and propagate.