Reuven Agami

Oncogenomics

The identification of novel cellular vulnerabilities can be exploited for therapy. For this purpose, we develop innovative genomic and genetic tools and use them to identify cancer vulnerabilities. Key topics are protein production and the non-coding genome.

Pataskar et al., Nature, 2022

Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Activated T cells infiltrating the tumour microenvironment secrete interferon-γ (IFNγ) that induces expression of the enzyme IDO1 in cancer cells. IDO1 catabolizes tryptophan to subvert T cell immunity. In this paper we showed that despite tryptophan depletion protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process. We coined these W>F peptides ‘substitutants’ to distinguish them from genetically encoded mutants. Substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.

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Champagne et al., Molecular Cell, 2021

Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Such tryptophan shortage conditions stimulate the production of aberrant proteins by ribosomal frameshifting and codon reassignment events at tryptophan codons. We termed this phenomenon “sloppiness in mRNA translation” and strikingly observed its association with hyperactivation of the MAPK pathway. Functionally, sloppiness-induced events can impair protein activity, but also expand the landscape of antigens presented at the cell surface. These aberrant neoepitopes activate T cell responses, and thus can potentially be used to improve tumor immunoreactivity.

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Bartok et al., Nature, 2021

Anti-tumour immunity induces aberrant peptide presentation in melanoma

Here we collaborated with the group of Yardena Samuels at the WIS, Israel, to investigate why a promising immunosuppressive drug does not work in a clinical setting. Activated T cells infiltrating the tumour microenvironment secrete interferon-γ (IFNγ) that induces IDO1. IDO1 catabolizes tryptophan to subvert T cell immunity. Clinical trials using IDO1 inhibitors in combination with blockade of the PD1 pathway in patients with melanoma did not improve treatment efficacy compared to PD1 pathway blockade alone. Our results suggest that IDO1-mediated depletion of tryptophan has a role in the immune recognition of melanoma cells by contributing to the diversification of the peptidome landscape.

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Slobodin et al., Cell, 2017

Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation

Transcription and translation are two main pillars of gene expression. Due to the different timings, spots of action, and mechanisms of regulation, these processes are mainly regarded as distinct and generally uncoupled, despite serving a common purpose. Here, we sought for a possible connection between transcription and translation. Employing an unbiased screen of multiple human promoters, we identified a positive effect of TATA box on translation and a general coupling between mRNA expression and translational efficiency. Our study uncovers a general and widespread link between transcription and translation that is governed by epigenetic modification of mRNAs.

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Loayza-Puch et al., Nature, 2016

Tumour-specific proline vulnerability uncovered by differential ribosome codon reading

Tumour growth and metabolic adaptation may restrict the availability of certain amino acids for protein synthesis. It has recently been shown that certain types of cancer cells depend on glycine, glutamine, leucine and serine metabolism to proliferate and survive. However, a tailored detection system for measuring restrictive amino acids in each tumour is currently unavailable. In this paper, we harnessed ribosome profiling for sensing restrictive amino acids, and develop diricore, a procedure for differential ribosome measurements of codon reading.

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Korkmaz et al., Nature Biotechnology 2016

Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9

Systematic identification of noncoding regulatory elements has, to date, mainly relied on large-scale reporter assays that do not reproduce endogenous conditions. We present two distinct CRISPR-Cas9 genetic screens to identify and characterize functional enhancers in their native context. Our strategy is to target Cas9 to transcription factor binding sites in enhancer regions. We identified several functional enhancer elements and characterized the role of two of them in mediating p53 (TP53) and ERα (ESR1) gene regulation. Moreover, we show that a genomic CRISPR-Cas9 tiling screen can precisely map functional domains within enhancer elements. Our approach expands the utility of CRISPR-Cas9 to elucidate the functions of the noncoding genome.

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Lisa Dicke Office Manager

+31 20 512 2015 l.dicke@nki.nl

Reuven Agami

Oncogenomics

alumni

Anti-tumour immunity induces aberrant peptide presentation in melanoma

Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation

Tumour-specific proline vulnerability uncovered by differential ribosome codon reading

Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9

MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer.

ABPEPserver: a web application for documentation and analysis of substitutants.

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