The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets.

Abstract

The resistance to transcription factor-mediated reprogramming into pluripotent stem cells is one of the distinctive features of cancer cells. Here we dissect the profiles of reprogramming factor binding and the subsequent transcriptional response in cancer cells to reveal its underlying mechanisms. Using clear cell sarcomas (CCSs), we show that the driver oncogene EWS/ATF1 misdirects the reprogramming factors to cancer-specific enhancers and thereby impairs the transcriptional response toward pluripotency that is otherwise provoked. Sensitization to the reprogramming cue is observed in other cancer types when the corresponding oncogenic signals are pharmacologically inhibited. Exploiting this oncogene dependence of the transcriptional "stiffness," we identify mTOR signaling pathways downstream of EWS/ATF1 and discover that inhibiting mTOR activity substantially attenuates the propagation of CCS cells in vitro and in vivo. Our results demonstrate that the early transcriptional response to cell fate perturbations can be a faithful readout to identify effective therapeutics targets in cancer cells.

• Authors: Kenji Ito, Kohei Nagata, Sho Ohta, Yutaka Matsuda, Tomoyo Ukai, Ichiro Yasuda, Akira Ota, Ryota Kobayashi, Mio Kabata, Nao Sankoda, Tatsuya Maeda, Knut Woltjen, Liying Yang, Reo Maruyama, Ryohei Katayama, Takuya Yamamoto, Yasuhiro Yamada
• Journal: Cell reports (Cell Rep) Vol. 39 Issue 4 Pg. 110721 (04 26 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35476996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Transcription Factors
• TOR Serine-Threonine Kinases

Topics

• Humans
• Oncogenes
• Sarcoma, Clear Cell (genetics)
• Signal Transduction
• TOR Serine-Threonine Kinases
• Transcription Factors (genetics)