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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
09:58

Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models

Published on: December 9, 2016

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Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance

Sydney M Shaffer1,2, Margaret C Dunagin1, Stefan R Torborg1,3

  • 1Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Nature
|June 14, 2017
PubMed

Insights

Cancer cells can spontaneously develop drug resistance through rare transcriptional changes. Drug treatment then locks in this resistance via epigenetic reprogramming, highlighting a multistage process in rare cell populations.

Area of Science:

  • Oncology
  • Cell Biology
  • Genetics

Background:

  • Targeted cancer therapies show initial efficacy but are limited by acquired drug resistance.
  • The emergence of resistant cancer cells, a major hurdle in achieving cures, can stem from genetic mutations or non-genetic factors.
  • Non-genetic rare cell variability presents a potential mechanism for drug resistance independent of clear genetic alterations.

Purpose of the Study:

  • To investigate single-cell transcriptional variability in human melanoma.
  • To determine if this variability predicts which cells will resist drug treatment.
  • To elucidate the mechanisms underlying the multistage acquisition of drug resistance.

Main Methods:

  • Single-cell RNA sequencing to analyze transcriptional variability.
  • Drug treatment experiments to observe resistance development.
  • Epigenetic analysis to study reprogramming events.

Main Results:

  • Human melanoma cells exhibit significant single-cell transcriptional variability.
  • This variability predicts subsequent drug resistance in a subpopulation of cells.
  • Drug treatment induces epigenetic reprogramming, stabilizing transient resistance states by altering differentiation (SOX10 loss) and activating new signaling pathways (JUN, AP-1, TEAD).

Conclusions:

  • Drug resistance in cancer is a multistage process involving initial rare cell transcriptional variability followed by drug-induced epigenetic reprogramming.
  • This mechanism, observed in melanoma, may represent a general program for resistance in rare cell subpopulations across different cell types.
  • Understanding these dynamics offers a framework for developing novel therapeutic strategies against cancer drug resistance.

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