2. Academic Validation
  3. Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer

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

  • Cell Stem Cell. 2020 Jun 4;26(6):845-861.e12. doi: 10.1016/j.stem.2020.04.012.
Clara Morral 1,  Jelena Stanisavljevic 1,  Xavier Hernando-Momblona 2,  Elisabetta Mereu 3,  Adrián Álvarez-Varela 2,  Carme Cortina 2,  Diana Stork 1,  Felipe Slebe 1,  Gemma Turon 1,  Gavin Whissell 1,  Marta Sevillano 2,  Anna Merlos-Suárez 1,  Àngela Casanova-Martí 1,  Catia Moutinho 3,  Scott W Lowe 4,  Lukas E Dow 5,  Alberto Villanueva 6,  Elena Sancho 2,  Holger Heyn 7,  Eduard Batlle 8
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain.
  • 2 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain.
  • 3 CNAG-Centre for Genomic Regulation (CRG), BIST, Baldiri i Reixac 4, 08028 Barcelona, Spain.
  • 4 Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • 5 Department of Medicine, Weill-Cornell Medical College, New York, NY 10021, USA.
  • 6 Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
  • 7 CNAG-Centre for Genomic Regulation (CRG), BIST, Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  • 8 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain. Electronic address: [email protected].
PMID: 32396863 DOI: 10.1016/j.stem.2020.04.012
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 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.

Keywords

CRC; Cancer Stem Cell; biosynthetic capacity; plasticity; stem cell hierarchy.

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