Circadian gene trafficking: A new paradigm in cancer evolution

This proposal explores the molecular mechanisms by which deregulation of circadian 3D epigenome organisation fuels phenotypic plasticity and adaptability of breast cancer cells.

It builds on my recent hypothesis that increased stochastic epigenetic variation in cancer is promoted by altered gene mobility between different nuclear sub-compartments that have instructive functions on chromatin states.

I coin here this principle as “gene trafficking” to highlight the regulated migration of genes between sub-nuclear compartments.

The resulting increased stochastic epigenetic variation is hypothesised to be translated into fluctuations in the composition of the transcriptome/proteome of the tumor cells to facilitate switches between cell states with increased or decreased developmental potential, typical of phenotypic plasticity.

I also propose that the stochastic reactivation of the cellular machinery that unleashes phenotypic plasticity is facilitated by the peripheral localisation of their normally repressed genes in somatic progenitor cells/mature cell states.

Since gene trafficking to nuclear pores is under circadian control, the research plan aims to establish cause-and-effect relationships between the frequent deregulation of the 3D nuclear architecture and circadian perturbations in tumors.

Aim1: To dissect the mechanisms of cancer cell-specific gene trafficking in the 3D nucleusAim2: To explore cell-to-cell heterogeneity in gene trafficking as a driver of cancer evolution