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The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets

Kenji Ito1, Kohei Nagata2, Sho Ohta1

  • 1Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

Cell Reports
|April 27, 2022
PubMed

Insights

Cancer cells resist reprogramming due to oncogenes like EWS/ATF1. Inhibiting mTOR signaling, identified through this resistance, effectively halts clear cell sarcoma progression.

Area of Science:

  • Oncology
  • Stem Cell Biology
  • Molecular Biology

Background:

  • Cancer cells exhibit resistance to reprogramming into pluripotent stem cells.
  • Understanding the mechanisms of this resistance is crucial for cancer therapy.
  • Oncogenic signaling pathways play a role in maintaining cancer cell identity.

Purpose of the Study:

  • To dissect the mechanisms underlying cancer cell resistance to transcription factor-mediated reprogramming.
  • To identify novel therapeutic targets by analyzing the transcriptional response to reprogramming cues in cancer cells.
  • To investigate the role of specific oncogenes, such as EWS/ATF1, in this resistance.

Main Methods:

  • Analysis of reprogramming factor binding profiles in cancer cells.
  • Assessment of transcriptional responses to reprogramming factors.
  • Utilizing clear cell sarcomas (CCSs) as a model system.
  • Pharmacological inhibition of oncogenic signaling pathways.
  • Identification of downstream signaling pathways, including mTOR.
  • In vitro and in vivo experiments to evaluate therapeutic interventions.

Main Results:

  • The oncogene EWS/ATF1 misdirects reprogramming factors to cancer-specific enhancers, impairing pluripotency induction.
  • Inhibition of oncogenic signals sensitizes other cancer types to reprogramming cues.
  • mTOR signaling pathways were identified downstream of EWS/ATF1.
  • Inhibition of mTOR activity significantly reduced the proliferation of CCS cells in vitro and in vivo.

Conclusions:

  • The transcriptional response to cell fate perturbations serves as a reliable indicator for identifying effective cancer therapeutics.
  • Targeting oncogene-dependent transcriptional stiffness, such as through mTOR inhibition, offers a promising therapeutic strategy for clear cell sarcomas.
  • This study reveals a novel vulnerability in cancer cells related to their resistance to reprogramming.
Keywords:
CP: CancerMyoD1OSKMcancer cell identitycancer therapeuticsdriver oncogenic signalreprogrammingresistance to reprogrammingtranscriptional response

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