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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

p53 Orchestrates the Immunogenic-Tolerogenic Pyroptosis Switch in Non-Small Cell Lung Cancer: A Systems Biology

Shantanu Gupta1, Daner A Silveira2, Rodrigo Juliani Siqueira Dalmolin1

  • 1Bioinformatics Multidisciplinary Environment-BioME-Digital Metropole Institute, Federal University of Rio Grande do Norte, Natal 59076550, RN, Brazil.

Computational and Structural Biotechnology Journal
|July 22, 2026
PubMed

Insights

Tumor suppressor p53 regulates cell death pathways in non-small cell lung cancer (NSCLC). A new model reveals p53 controls a switch between pyroptosis and apoptosis, impacting therapy resistance.

Area of Science:

  • Cellular biology
  • Cancer research
  • Systems biology

Background:

  • Therapy failure in non-small cell lung cancer (NSCLC) is linked to resistance to immunogenic cell death.
  • The tumor suppressor p53 can initiate two distinct pyroptosis pathways: canonical (NLRP3-caspase-1-GSDMD) and secondary (caspase-9/3-GSDME).
  • The coordination logic of these parallel p53-regulated cell death pathways is not well understood, hindering therapeutic strategies.

Purpose of the Study:

  • To elucidate the systems-level logic governing p53-regulated pyroptosis pathways in NSCLC.
  • To model the decision-making process that directs cell death outcomes.
  • To identify therapeutic targets for overcoming resistance to immunogenic cell death.

Main Methods:

  • Development of the first dynamic Boolean network model for p53-regulated pyroptosis in NSCLC.
  • Analysis of feedback loops governing the terminal caspase-gasdermin axis.
  • Validation of model predictions using NSCLC cell line phenotypes and patient transcriptomics.

Main Results:

  • The p53-regulated terminal caspase-gasdermin axis functions as a bistable immunogenic switch.
  • Interlocked feedback loops, including a double-negative motif and a reinforcing loop, control pathway mutual exclusivity and commitment to secondary pyroptosis.
  • Loss of GSDME, common in NSCLC, is predicted to redirect p53-activated caspase-3 towards apoptosis, explaining evasion of immunogenic lysis.
  • Coordinated repression of pyroptosis-execution genes and identification of CASP9/GSDME as adverse prognostic markers.

Conclusions:

  • p53 acts as a central coordinator of a terminal cell fate-switch network, not just a linear activator.
  • The study provides a systems-level framework for understanding how cell death execution circuits influence outcomes in NSCLC.
  • This framework can guide the development of novel therapeutic strategies targeting cell death pathways in NSCLC.

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