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MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung Cancer

Arnaud Augert1, Haritha Mathsyaraja2, Ali H Ibrahim1

  • 1Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA.

Cancer Cell
|May 30, 2020
PubMed

Insights

Loss of the MAX gene, a partner for MYC proteins, accelerates small cell lung cancer (SCLC) but can suppress tumors in specific contexts by altering cell metabolism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options.
  • Identifying novel tumor suppressors is crucial for developing effective SCLC treatments.

Purpose of the Study:

  • To identify candidate tumor suppressors in early-stage SCLC using CRISPR/Cas9 screening.
  • To investigate the role of MAX, a MYC-interacting protein, in SCLC development and progression.

Main Methods:

  • CRISPR/Cas9 gene inactivation screens were performed on a cellular model of early-stage SCLC.
  • The impact of MAX deletion on SCLC progression was assessed in an Rb1/Trp53-deleted mouse model.
  • Metabolic gene expression and serine biosynthesis were analyzed in MAX-deleted SCLC cells.

Main Results:

  • MAX was identified as a top hit in CRISPR/Cas9 screens for SCLC tumor suppressors.
  • Max deletion accelerated SCLC progression in an Rb1/Trp53-deleted mouse model.
  • Conversely, Max deletion abrogated tumorigenesis in MYCL-overexpressing SCLC and altered cellular metabolism, enhancing serine biosynthesis and conferring resistance to serine depletion.

Conclusions:

  • MAX functions as a context-specific tumor suppressor in SCLC.
  • Loss of MAX leads to metabolic rewiring, impacting SCLC tumorigenesis.
  • Targeting metabolic pathways in MAX-altered SCLC may offer therapeutic strategies.
Keywords:
CRISPR-Cas9 genetic screensMAXMYCSCLCTranscriptional regulationcancermouse modelserine and one-carbon metabolismsmall cell lung cancertumor suppressor genes

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