Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer

• DOI: 10.1016/j.stem.2020.04.012
• Publication Date: 2020-05-11T15:44:06Z
• Authors: Clara Morral; Jelena Stanisavlj...; Xavier Hernando-M...; Elisabetta Mereu; Adrián Álvarez-Va...; Carme Cortina; Diana Stork; Felipe Slebe; Gemma Turon; Gavin Whissell; Marta Sevillano; Anna Merlos-Suárez; Àngela Casanova-M...; Catia Moutinho; Scott W. Lowe; Lukas E. Dow; Alberto Villanueva; Elena Sancho; Holger Heyn; Eduard Batlle
• Keywords: Transcripció genètica; Càncer colorectal; Genetic transcription; Cell Line, Tumor; Neoplastic Stem Cells; Humans; Stem cells; Cèl·lules mare; Colorectal Neoplasms; Colorectal cancer; DNA, Ribosomal; Receptors, G-Protein-Coupled; 3. Good health

Colorectal cancers (CRCs) are composed of an amalgam of cells with distinct genotypes and phenotypes. Here, we reveal a previously unappreciated heterogeneity in the biosynthetic capacities of CRC cells. We discover that the majority of ribosomal DNA transcription and protein synthesis in CRCs occurs in a limited subset of tumor cells that localize in defined niches. The rest of the tumor cells undergo an irreversible loss of their biosynthetic capacities as a consequence of differentiation. Cancer cells within the biosynthetic domains are characterized by elevated levels of the RNA polymerase I subunit A (POLR1A). Genetic ablation of POLR1A-high cell population imposes an irreversible growth arrest on CRCs. We show that elevated biosynthesis defines stemness in both LGR5+ and LGR5- tumor cells. Therefore, a common architecture in CRCs is a simple cell hierarchy based on the differential capacity to transcribe ribosomal DNA and synthesize proteins.