Thursday, April 25, 2024
4/25/2024
¿ DESCRIPTION (provided by applicant): The ability of cancer cells to adapt to a wide variety of stress conditions plays a critical role in various physiological facets of tumorigenesis. We recently reported the discovery of a class of stress-induced long noncoding RNAs derived from stimuli-specific loci of the ribosomal intergenic spacer (Mol. Cell (2012) 45:147), a puzzling region of the human genome historically assumed to be transcriptionally inactive. Induction of rDNA intergenic spacer RNA (IGSRNA) converts the nucleolus from a factory of ribosomes to the Nucleolar Detention Center: a molecular prison that immobilizes specific proteins in response to extracellular stressors (Nature Cell Biol. (2004) 6:642; J.Cell. Biol. (2005) 170:733; Mol. Biol. Cell. (2013) 24: 2943). The Nucleolar Detention Center is observed in cells that populate the core of human tumors and is induced by various cancer-related stressors, including extracellular acidosis and the anti-mitotic therapeutic doxorubicin. We will show preliminary data that the Nucleolar Detention Center comprises of a biochemically heterogeneous population of proteins including elements of the DNA synthesis machinery. Cancer cells activate IGSRNA- mediated nucleolar immobilization of proteins to reduce metabolism and withdraw from the cell cycle in an adaptive response to severe environmental insults. This raises the fascinating possibility that the IGSRNA are involved in the attainment of tumor cell dormancy, a critical phenotype in a cancer cell's ability to sustain viability in the hash conditions of the tumor microenvironment and resist anti-cancer therapy. Based on these aforementioned rationales, we propose the following hypothesis: Stimuli-specific formation of the Nucleolar Detention Center by IGSRNA induces tumor cell dormancy. In the Specific Aims, we will: 1- Survey the ribosomal intergenic spacer for IGSRNA induced by cancer-related stressors; 2- Examine the specific Nucleolar Detention Center proteomes as a function of various stress conditions; 3- Demonstrate a role for the IGSRNA-mediated Nucleolar Detention Center in the dormant tumor cell phenotype. The discovery of the IGSRNA-regulated Nucleolar Detention Center constitutes a unique and remarkable window of opportunity to investigate a largely unexplored post-translational mechanism potentially involved in tumor cell dormancy. These studies will yield significant conceptual advances in our understanding of critical adaptive/resistance processes exploited by cancer cells to sustain viability in the tumor microenvironment and resistance to anti- cancer drugs.
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