Genetic Modifiers of Initiation and Progression of Mammary Cancer

Division Of Basic Sciences - Nci

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Abstract

Over the past reporting period significant advances have been made in the understanding of the mechanistic basis for metastasis susceptibility. Building on previous observations that many of the independently identified metastasis susceptibility proteins physically interact within the nucleus, we have discovered that these proteins are responsive to stresses experienced by cells during tumor growth and progression. These stresses include increased mechanical load due to increases in tumor extracellular matrix, acidosis and hypoxia due to inadequate vascular and capillary perfusion of growing tumor masses as well as thermal stresses due to increased metabolic activity within the tumor. The metastasis susceptibility genes react to these environmental conditions in a gene- and stress-specific manner, suggesting that individual genes are fine-tuning cellular responses to individual stresses. Gene responses to these stresses include not only changes in gene transcription and translation, but also subnuclear localization transitions, primarily between the nuclear envelope, nucleolus and the nuclear speckle. The effects of these stress responses appear to primarily affect two different overlapping molecular mechanisms; the formation and efficient function of transcriptional biomolecular condensates and fine tuning of transcriptional output through alterations of messenger RNA splicing. Preliminary evidence suggests that the metastasis susceptibility genes contribute to tumor cell plasticity through these mechanisms, allowing tumor cells to rapidly adapt to changing conditions within the primary tumor, as well as during dissemination and adaptation at the secondary site. Identification of molecular mechanisms by which the metastasis susceptibility proteins mediate these effects may provide novel targets for clinical exploitation. For example, inhibiting potential post-translational modifications that mediate subnuclear localization transitions might prevent successful adaptation during metastatic progression, reducing overall tumor burden for improved patient outcome.