Amyloid-bodies and the Evolution of Malignancies

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Amyloid-bodies and the Evolution of Malignancies Project Summary 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 stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as “junk” DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts nucleoli into Amyloid-bodies: reversible nuclear membrane-less compartments composed of immobilized proteins in an amyloid-like state. While many cellular bodies have been described as liquid-like (e.g., stress granules, P-bodies, germ cell granules), the discovery of Amyloid-bodies provided evidence of an amyloidogenic program that can physiologically transition biological matter to a solid state. Amyloid-bodies are found in sub-populations of cells in normal tissues, the core of low- grade human tumors and cells responding to various stimuli highlighting their ubiquitous nature. Proteomic analysis revealed that Amyloid-bodies immobilize participants of the DNA synthesis machinery and cell cycle control, amongst many other metabolic regulators. Intriguingly, Amyloid-bodies share many biophysical properties with the amyloidogenic, solid-like Balbiani-bodies involved in metabolic suppression in Xenopus. Likewise, yeast solidify elements of their proteome to sporulate and arrest growth in non-permissive conditions. This raises the fascinating possibility that stressed cancer cells assemble Amyloid-bodies to enter a spore-like state of extreme metabolic depression. In this grant proposal, we will show preliminary data that low complexity rIGSRNA coordinate unusual RNA tailing programs to drive system-wide amyloidogenic phase transition. This post-translational pathway enables cancer cells to immobilize elements of the DNA synthesis machinery and halt oncogenic signaling in an adaptive response to severe environmental insults. Based on these preliminary and published results, we hypothesize that “Nucleolar phase transition programs temporarily suspend oncogenicity”. We plan to test this hypothesis by: 1- Uncovering mechanisms of physiological phase transition; 2- Examining how low complexity rIGSRNA activate RNA tailing programs; 3- Demonstrating a role for RNA tailing-mediated phase transition in tumorigenesis. The discovery of dedicated enzymatic programs that drive physiological amyloidogenesis provides a unique opportunity to study the role of liquid-to-solid phase transition in human clinical samples and in vivo tumor assays. By studying clinical samples, in culture and orthotopic animal models, we will test if phase transition induces a unique and yet uncharacterized cancer cell state of extreme metabolic depression, while highlighting biochemical functions for low complexity RNA typically discarded as useless nucleic acids.