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 occur 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 1 subunit A - POLR1A. Genetic ablation of POLR1A-high cell population imposes an irreversible growth arrest to CRCs. We show that elevated biosynthesis defines stemness in both LGR5+ and LGR5- tumor cells. Therefore, a common architecture in CRC is a simple cell hierarchy based on the differential capacity to transcribe ribosomal DNA and synthesize proteins. Overall design: Full-length single cell RNA sequencing libraries were prepared using the Smart-seq2 protocol with minor modifications.