Dysregulated gene expression is a universal feature of cancer that drives malignant phenotypes and patient outcomes. A central determinant of gene expression is mRNA abundance, highlighting the delicate balance between mRNA synthesis and decay.

While extensive work has revealed mechanisms by which aberrations in mRNA synthesis drive cancer (ex. Myc transcription factors), comparatively little is understood about dysregulated RNA decay and its impact on gene expression and cancer pathogenesis. Ribonucleases are central players in all RNA decay processes. Large functional genomics studies have recently identified many of the 122 annotated human ribonucleases as selective cancer vulnerabilities...

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Dysregulated gene expression is a universal feature of cancer that drives malignant phenotypes and patient outcomes. A central determinant of gene expression is mRNA abundance, highlighting the delicate balance between mRNA synthesis and decay.

While extensive work has revealed mechanisms by which aberrations in mRNA synthesis drive cancer (ex. Myc transcription factors), comparatively little is understood about dysregulated RNA decay and its impact on gene expression and cancer pathogenesis. Ribonucleases are central players in all RNA decay processes. Large functional genomics studies have recently identified many of the 122 annotated human ribonucleases as selective cancer vulnerabilities, but the genetic- and tissue-contexts that create these selective cancer dependencies remain unexplored. This is compounded by a limited understanding of the mechanisms that govern ribonuclease RNA recognition and selective mRNA decay in cancer.

I propose to establish a cancer research program to systematically reveal how ribonucleases confer RNA specificity, how cancers exploit selective mRNA decay to reshape the transcriptome and uncover the molecular basis for ribonuclease dependencies in cancer. To do this, my laboratory will pursue the following goals:

1) Elucidate how ribonucleases shape the breast cancer transcriptome

2) Define the mechanisms of aberrant mitochondrial RNA turnover in breast cancer pathogenesis

3) Develop a platform for discovering chemical probes against ribonucleases to explore their roles as breast cancer dependencies.

Together, this multidisciplinary program will provide a framework to understand how ribonucleases dysregulate cancer gene expression and define their roles as selective cancer dependencies. My long term goal is to provide a foundation for the cancer community in studying and drugging this new class of cancer targets and exploiting these cancer vulnerabilities for the benefit of cancer patients.

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