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Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
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Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells

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Oncogenic context shapes the fitness landscape of tumor suppression

Lily M Blair1, Joseph M Juan1, Lafia Sebastian1

  • 1D2G Oncology, Mountain View, CA, USA.

Nature Communications
|October 12, 2023
PubMed

Insights

Tumor suppressor gene inactivation effects vary with oncogene context, revealing a complex cancer fitness landscape. This highlights crucial off-axis signaling in tumor development, not just linear pathways.

Area of Science:

  • Oncology
  • Cancer Genomics
  • Systems Biology

Background:

  • Tumorigenesis involves oncogene and tumor suppressor gene alterations.
  • Interactions shaping the cancer fitness landscape are poorly understood.
  • Human cancer genomics alone cannot fully resolve these complex interactions.

Purpose of the Study:

  • To model and quantify lung tumor initiation and growth across diverse oncogenic contexts.
  • To investigate the fitness landscape of tumorigenesis.
  • To elucidate the role of tumor suppressor gene inactivation in different oncogenic backgrounds.

Main Methods:

  • Utilized a multiplexed, autochthonous mouse model.
  • Generated and analyzed over one hundred lung tumor genotypes.
  • Focused on four key oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R.

Main Results:

  • Demonstrated a rugged cancer fitness landscape where tumor suppressor inactivation effects are context-dependent.
  • Observed no diminishing-returns epistasis within variants of the same oncogene.
  • Found that oncogene interactions are not simply linear.

Conclusions:

  • The fitness landscape of tumorigenesis is complex and context-specific.
  • Tumor suppressor gene function is critically influenced by the specific oncogene driving tumor initiation.
  • Off-axis signaling pathways play a significant role in determining the fitness impact of tumor suppressor inactivation.

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