Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer.
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.
['Morral|Clara|C|', 'Stanisavljevic|Jelena|J|', 'Hernando-Momblona|Xavier|X|', 'Mereu|Elisabetta|E|', 'Álvarez-Varela|Adrián|A|', 'Cortina|Carme|C|', 'Stork|Diana|D|', 'Slebe|Felipe|F|', 'Turon|Gemma|G|', 'Whissell|Gavin|G|', 'Sevillano|Marta|M|', 'Merlos-Suárez|Anna|A|', 'Casanova-Martí|Àngela|À|', 'Moutinho|Catia|C|', 'Lowe|Scott W|SW|', 'Dow|Lukas E|LE|', 'Villanueva|Alberto|A|', 'Sancho|Elena|E|', 'Heyn|Holger|H|', 'Batlle|Eduard|E|']
D045744:Cell Line, Tumor D015179:Colorectal Neoplasms D004275:DNA, Ribosomal D006801:Humans D014411:Neoplastic Stem Cells D043562:Receptors, G-Protein-Coupled
stem cell hierarchy CRC biosynthetic capacity Cancer Stem Cell plasticity