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Molecular phenotyping of colorectal neoplasia shows dynamic and adaptive cancer stem cell population admixture

bioRxiv, ISSN: 2692-8205
2022
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Article Description

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterised by fetal transcriptional profiles. Neoplasia hijacks regenerative signalling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signalling disruption, and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis, and is influenced by cell-intrinsic, extrinsic and therapeutic selective pressures.

Bibliographic Details

Ester Gil Vazquez; Nadia Nasreddin; Gabriel N. Valbuena; Eoghan J. Mulholland; Hayley L. Belnoue-Davis; Holly Eggington; Ryan O. Schenck; Sulochana Omwenga; Simon J. Leedham; Valérie M. Wouters; David J. Huels; Pratyaksha Wirapati; Kathryn Gilroy; Tamsin R.M. Lannagan; Dustin J. Flanagan; Arafath K. Najumudeen; Andrew D. Campbell; Owen Sansom; Amy M.B. McCorry; Maurice B. Loughrey; Philip D. Dunne; Alistair Easton; Timothy Maughan; Viktor H. Koelzer; James E. East; Dion Morton; Livio Trusolino; Petros Tsantoulis; Sabine Tejpar

Cold Spring Harbor Laboratory

Biochemistry, Genetics and Molecular Biology; Agricultural and Biological Sciences; Immunology and Microbiology; Neuroscience; Pharmacology, Toxicology and Pharmaceutics

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