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

Abstract

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.

Ribosome Biogenesis Alterations in Colorectal Cancer

“…BMH-21 activates a rapid p53-dependent cytotoxic effect with little associated DNA damage in many human cancer cell lines, including HCT-116 CRC cells, yand is also very potent in inhibiting HCT- 116 xenograft growth in mice [190]. Very interestingly, it was recently reported that CRC patient-derived xenografts contain a sub-population of cancer stem cells characterized by high expression levels of the RNA pol I subunit A (PolR 1 A) and elevated biosynthetic capacities [191]. Besides, PolR 1 A is shown as one of the prerequisites for in vivo tumor growth [191].…”

“…Very interestingly, it was recently reported that CRC patient-derived xenografts contain a sub-population of cancer stem cells characterized by high expression levels of the RNA pol I subunit A (PolR 1 A) and elevated biosynthetic capacities [191]. Besides, PolR 1 A is shown as one of the prerequisites for in vivo tumor growth [191]. CRC stem cells with high expression of PolR 1 A were classified at the top of tumor stem cell hierarchy and ip injection of BMH-21 induced a significant decrease in PolR 1 A-high stem cell and in tumor xenograft growth [191].…”

“…Besides, PolR 1 A is shown as one of the prerequisites for in vivo tumor growth [191]. CRC stem cells with high expression of PolR 1 A were classified at the top of tumor stem cell hierarchy and ip injection of BMH-21 induced a significant decrease in PolR 1 A-high stem cell and in tumor xenograft growth [191]. In addition, it appears that the FDA-approved antimalarial drug amodiaquine was recently shown to block rDNA transcription and proliferation of various human CRC cells lines by a mechanism very close to the induction of ribosome biogenesis stress and cell death by BMH-21 [192].…”

Intestinal epithelial plasticity and regeneration via cell dedifferentiation

“…Furthermore, the dietary-responsive phospholipid-cholesterol axis regulates ISC proliferation (Wang et al 2018 ). More recently, Morral et al discovered that zonation of rDNA/protein synthesis could define a stem cell hierarchy colorectal cancers (Morral et al 2020 ). Quiescent stem cells have been indicated to be in the minimal metabolic requirements (Signer et al 2014 ; Simsek et al 2010 ).…”

Lipid-Based Drug Delivery Nanoplatforms for Colorectal Cancer Therapy

“…Unlike regular cancer cells, CCSCs appear to replicate slowly; thus, they can escape formulations that target quickly replicating cells. Fortunately, some populations of CCSCs can be characterized by their specifically expressed biomarkers, such as CD133, CD44, CD166, EpCAM, and Lgr5 [ 149 , 150 , 151 , 152 ]. Targeting one or more of these biomarkers could offer a practical approach for effectively delivering anticancer drugs to CCSCs.…”