Understanding how cancers up-regulate their synthesis of ribosome to support growth and proliferation The synthesis of ribosome is aberrantly increased in almost all cancers. The rate-limiting step in ribosome biogenesis is the production of the ribosomal RNA (rRNA), which is found dramatically unregulated in cancers. Strikingly, tumors are found to be much more sensitive than normal cells to the inhibition of rRNA production, indicating that pathways involved in the regulation of rRNA synthesis constitute a therapeutic vulnerability for cancers. Our goal is to identify novel means to block rRNA synthesis to limit the proliferation and survival of cancer cells. A critical barrier to developing affective inhibitor of rRNA synthesis is our poor understanding of the molecular mechanisms responsible for the aberrant regulation of rRNA production in cancers. Thus, a lot of our projects are focused on identifying novel pathways and key regulators of rRNA transcription in cancer cells. We recently uncovered that the transcriptional regulator and oncogene Pelp1 is part of an essential rRNA processing complex required for the production of the 28S rRNA. We are currently identifying the mechanisms by which Pelp1 regulates rRNA synthesis during breast cancer development.
Understanding how rRNA modification support growth and proliferation Emerging evidence indicate that cancers also produce specialized ribosomes that selectively translate a proteome supporting cellular transformation and tumor development. One mechanism by which this alteration in ribosome function occurs in cancer is through aberrant changes in the methylation pattern of the rRNA. Because the rRNA constitutes the catalytic core of the ribosome, methylation of its residue directly affects translation accuracy and specificity towards certain types of mRNAs. Although several rRNA methyltransferases are found overexpressed in cancers, pathways regulating their function as well as how their activity shapes the cancer proteome are poorly understood. Our goal is to identify breast cancer-specific rRNA methylation patterns and determine how these changes influence ribosome function. We are particularly interested in identifying mRNAs preferentially translated by these cancer-specific ribosomes.
Understanding how tRNA modifications induces translational reprogramming in cancer
The recent strides in mapping the epitranscriptome have unveiled the complex landscape of RNA modifications and their essential role in gene expression regulation. Among cellular RNAs, tRNAs emerge as particularly intricate, often harboring an average of 10-13 modifications per molecule. These modifications govern pivotal tRNA functions, including ensuring decoding accuracy, and maintaining structural integrity, all essential for enabling precise and efficient mRNA translation. Dysregulation of tRNA modifications has been linked to aberrant mRNA translation programs associated with various cancer types. Although the expression of several tRNA modifying enzymes is deregulated in cancers, the molecular mechanisms by which their hypo- or hyper-activity shapes the tumor proteome remain inadequately understood. Our overarching objective is to uncover the intricate pathways and key enzymes governing different tRNA modifications, elucidating how this regulatory network supports tumorigenesis, thereby providing novel insights into how tRNA modifications drive translational reprogramming in cancer.