The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets

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.

Automated summary

Resistance to transcription factor-mediated reprogramming into pluripotent stem cells is a distinctive feature of cancer cells, but studying the profiles of reprogramming factor binding and transcriptional response can reveal underlying mechanisms and potential therapeutic targets. In cancer cells, oncogenes like EWS/ATF1 can misdirect reprogramming factors to specific enhancers, inhibiting the transcriptional response towards pluripotency. Pharmacological inhibition of corresponding oncogenic signals can sensitize cancer cells to reprogramming cues, while targeting downstream signaling pathways like mTOR can attenuate cancer cell propagation. This highlights the potential for early transcriptional responses to guide the identification of effective therapeutics targets in cancer cells.