Preprint: tumour microenvironment shapes which gene–gene interactions drive metastatic fitness

A preprint posted to bioRxiv describes a study in which researchers mapped gene-by-gene-by-environment (GxGxE) interactions in a lung metastasis model by combining combinatorial CRISPR perturbation of tumour cell genomes with depletion of defined host myeloid cell populations in mice.

The central finding is that epistasis — the non-additive interaction between genetic loci — is not a fixed property of a tumour genome but is instead shaped by the tissue niche in which disseminated tumour cells find themselves. The metastatic niche first selects disseminated tumour cells based on their GxG epistatic fitness profile, then drives convergence of the transcriptome across surviving cells regardless of their underlying genotype. Removing anatomically localised myeloid populations altered which epistatic combinations were selected, demonstrating that host immune composition is part of the epistatic environment.

The work is relevant to researchers in cancer genomics, tumour immunology, and quantitative genetics, and has implications for understanding why the same oncogenic mutations can have different outcomes in different metastatic sites. It also raises methodological questions for the design of combinatorial genetic screens in cancer, which have typically been performed in uniform culture conditions rather than in niche-matched in vivo settings.

This is a preprint and has not yet been peer-reviewed.