Kong Yanjun, Gimple Ryan C, McVicar Rachael N, Hodges Andrew P, Yin Jun, Liu Yang, Zhan Weiwei, Snyder Evan Y
Department of Imaging and Nuclear Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, CA, USA.
Stem Cell Reports. 2020 Sep 8;15(3):761-775. doi: 10.1016/j.stemcr.2020.07.016. Epub 2020 Aug 13.
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.
一种理解组织特异性癌症如何产生的方法是确定将此类肿瘤细胞“重编程”回其发育正常的原始恶性前外胚层样多能状态的要求，然后仔细观察它们自发转化为肿瘤的过程，这可能会凸显最早的关键致癌途径（在成年肿瘤中积累其他畸变之前）。对于典型的恶性肿瘤间变性甲状腺癌（ATC），我们发现持续性RAS降低是将癌细胞重编程为模拟正常外胚层细胞的必要条件，这通过它们的转录组和表观遗传图谱的变化、肿瘤行为的丧失以及从其“外胚层类器官”中产生正常体细胞的能力得到证实。没有这种抑制，ATC会从克隆中重新出现。因此，对于ATC，RAS抑制是其“重编程启用”（RE）因子。每种癌症可能都有自己的RE因子；识别它可能会阐明恶性前风险标志物、更好的分类、治疗靶点以及先前多能、现在肿瘤性细胞的组织特异性。
