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 the reprogramming factor binding and the subsequent transcriptional response in cancer cells to reveal the molecular mechanisms underlying this phenomenon. Using clear cell sarcomas (CCSs) as a model, we show that expression of the driver oncogene EWS/ATF1 misdirects the reprogramming factors to cancer-specific enhancer elements and thereby impairs the early transcriptional response toward pluripotency which is otherwise provoked. Consistently, sensitization to the reprogramming cue is also observed in other types of cancer when the corresponding oncogenic signals are pharmacologically inhibited. Exploiting this oncogene dependence of the transcriptional ?stiffness?, we identify the mTOR signaling pathway downstream of EWS/ATF1, and discover inhibiting the mTOR activity substantially attenuates the propagation of CCS cells both in vitro and in vivo. Collectively, our results demonstrate that the early transcriptional response to cell fate perturbations can be a faithful readout to identify effective therapeutics in cancer cells. Moreover, the current study has implications for understanding how the cancer cell identity is robustly maintained. Overall design: Analyzing transcriptional profiles by RNA-seq for cancer cell reprogramming