Causes and consequences of aberrant mRNA translation in cancer

Introduction

Shortages in amino acids are weapons in the warfare between tumor cells and tumor-infiltrating lymphocytes. Tumor cells enhance or inhibit the production of key amino acid metabolites to stimulate oncogenesis and suppress anti-tumor activity. A key player in this battle is tryptophan.

Mechanism of Action

Activated T cells secrete interferon-γ, which upregulates the IDO1 enzyme to catabolize tryptophan to kynurenine in target tumor cells. While kynurenine suppresses T-cell function, its production limits tryptophan availability in tumor cells.

Consequences of Tryptophan Shortage

Importantly, as tumor cells almost invariably deregulate mRNA translation to promote proliferation and metastasis, the consequences of tryptophan shortage are major. It provokes aberrant mRNA translation at tryptophan codons, resulting in:

1. Ribosomal frameshifting
2. Tryptophan to phenylalanine (W>F) codon reassignments (substitutants)

This aberrant mRNA translation alters protein function and enriches the landscape of neoepitopes at the surface of tumor cells. Based on these observations, I hypothesize that the detection of aberrant proteins in cancer specimens can reveal additional key processes of cancer progression beyond tryptophan that can be utilized for cancer therapy.

Work Packages

To explore this exciting new idea, I designed three work packages (WPs):

• WP1: Expand the landscape of aberrant mRNA translation in cancer and link them to cancerous events. Preliminary results pinpoint arginine, histidine, and leucine.

• WP2: Generate reporter assays, set up functional genetic screens, and identify, validate, and explore key regulators of aberrant mRNA translation.

• WP3: Study the functional consequences of aberrant mRNA translation and introduce novel therapeutic concepts.

Conclusion

Altogether, this proposal will employ our recent discoveries of aberrant mRNA translation during periods of amino acid shortages to explore novel interplays between cancers and their suppressive microenvironment, and utilize this new knowledge for cancer therapy.