Stem Cell Reports 2020 09 13;15(3):761-775. Epub 2020 Aug 13.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA; Department of Pediatrics, University of California, La Jolla, CA, USA. Electronic address:
One approach to understanding how tissue-specific cancers emerge is to determine the requirements for "reprograming" such neoplastic cells back to their developmentally normal primordial pre-malignant epiblast-like pluripotent state and then scrutinizing their spontaneous reconversion to a neoplasm, perhaps rendering salient the earliest pivotal oncogenic pathway(s) (before other aberrations accumulate in the adult tumor). For the prototypical malignancy anaplastic thyroid carcinoma (ATC), we found that tonic RAS reduction was obligatory for reprogramming cancer cells to a normal epiblast-emulating cells, confirmed by changes in their transcriptomic and epigenetic profiles, loss of neoplastic behavior, and ability to derive normal somatic cells from their "epiblast organoids." Without such suppression, ATCs re-emerged from the clones. Hence, for ATC, RAS inhibition was its "reprogram enablement" (RE) factor. Each cancer likely has its own RE factor; identifying it may illuminate pre-malignant risk markers, better classifications, therapeutic targets, and tissue-specification of a previously pluripotent, now neoplastic, cell.