1. "Reprogram Enablement" as an Assay for Identifying Early Oncogenic Pathways by Their Ability to Allow Neoplastic Cells to Reacquire an Epiblast State.
- Author
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Kong Y, Gimple RC, McVicar RN, Hodges AP, Yin J, Liu Y, Zhan W, and Snyder EY
- Subjects
- Cell Differentiation genetics, DNA Methylation genetics, Down-Regulation genetics, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Germ Layers metabolism, Humans, Induced Pluripotent Stem Cells metabolism, Mutation genetics, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Phenotype, Sendai virus physiology, Thyroid Carcinoma, Anaplastic pathology, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Transcription, Genetic, ras Proteins genetics, ras Proteins metabolism, Biological Assay methods, Carcinogenesis pathology, Cellular Reprogramming genetics, Germ Layers pathology, Neoplasms pathology
- Abstract
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., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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