March 29, 1994 - March 29, 2027

  • Date:30TuesdayNovember 2021

    The epigenetic landscape of cancer-associated fibroblasts

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    Time
    10:00 - 10:30
    Location
    Nella and Leon Benoziyo Building for Biological Sciences
    Cafeteria
    Lecturer
    Coral Halperin
    Dept. of Biomolecular Sciences-WIS
    Organizer
    Department of Biomolecular Sciences
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    AbstractShow full text abstract about Cancer cells recruit and rewire normal cells in their microe...»
    Cancer cells recruit and rewire normal cells in their microenvironment to support and protect them by creating a pro-tumorigenic tumor microenvironment (TME). We lack an overarching view of how, despite being genomically stable, stromal cells in the tumor microenvironment are heterogeneously reprogrammed across time and space to promote the evolution of aggressive disease. Recent work by us and others has shown that fibroblasts in the tumor microenvironment are transcriptionally rewired to become protumorigenic cancer associated fibroblasts (CAFs). Here we hypothesize that CAFs are epigenetically modified and that these modifications lead to deregulation of signaling pathways and transcriptional circuitries that support tumorigenic growth in the neoplastic cells. We applied a sensitive method of whole genome bisulfide sequencing on a model of triple-negative breast cancer in mice to evaluate the methylome profile of CAFs compared to normal mammary fibroblasts (NMFs). We detected global changes in DNA methylation as well as distinct changes in promoter methylation between NMFs and breast CAFs in mice. These changes inversely correlated with transcriptional changes between CAFs and NMFs. We characterized potential regulators of this process, and tested their expression in CAFs in human breast cancer patients, to confirm relevance of our findings to human disease. Our findings suggest that epigenetic alterations contribute to the transcriptional rewiring of fibroblasts to CAFs. This work presents a comprehensive map of DNA-methylation in CAFs, and reveals a previously unknown facet of the dynamic plasticity of the stroma.


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