“Reprogram Enablement” as an Assay for Identifying Early Oncogenic Pathways by Their Ability to Allow Neoplastic Cells to Reacquire an Epiblast State

• Published in: Stem cell reports 2020-09, Vol.15 (3), p.761-775
• Main Authors: Kong, Yanjun, Gimple, Ryan C., McVicar, Rachael N., Hodges, Andrew P., Yin, Jun, Liu, Yang, Zhan, Weiwei, Snyder, Evan Y.
• Format: Article
• Language: English
• Subjects: cancer; cancer stem cells; epiblast; human embryonic stem cells; human induced pluripotent stem cells; oncogenesis; organoids; RAS; reprogram enablement; reprogramming; tumor
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2020.07.016

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. •The factors for reprogramming a cancer cell to an epiblast-like cell can be assayed•“Reprogram enablement” can yield insights into the earliest pivotal oncogenic steps•For anaplastic thyroid carcinoma, RAS inhibition was obligatory for reprograming•Each tissue-specific cancer will have its own reprogramming enablement requirement In this article, Snyder and colleagues show that the minimal essential factor(s) needed to convert a cancer cell back to its normal, pre-malignant, epiblast-like pluripotent state and then back again into a neoplastic cell—its “reprogram enablement factor”—may provide insights into the earliest pivotal steps in that cancer's tissue-specific oncogenesis, as well as its early diagnosis and treatment.