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. Display omitted •rRNA and proteins in CRCs are produced in dedicated tumor domains•Differentiated tumor cells experience an irreversible loss of biosynthetic capacities•POLR1A-high CRC cells reside at the top of the tumor cell hierarchy•Both LGR5+ and LGR5− tumor cells within biosynthetic niches fuel tumor growth Morral and colleagues discovered that most rRNA and proteins synthesized in colorectal cancers (CRCs) are contributed by a limited subset of tumor cells that reside adjacent to the stroma. This architecture defines a common stem cell hierarchy. In some CRCs, the biosynthetic tumor cell population renders LGR5+ tumor cells dispensable.