Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

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), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so...

Full description

Saved in:
Bibliographic Details
Published in:Cell stem cell 2022-08, Vol.29 (8), p.1213-1228.e8
Main Authors: Vasquez, Ester Gil, Nasreddin, Nadia, Valbuena, Gabriel N., Mulholland, Eoghan J., Belnoue-Davis, Hayley L., Eggington, Holly R., Schenck, Ryan O., Wouters, Valérie M., Wirapati, Pratyaksha, Gilroy, Kathryn, Lannagan, Tamsin R.M., Flanagan, Dustin J., Najumudeen, Arafath K., Omwenga, Sulochana, McCorry, Amy M.B., Easton, Alistair, Koelzer, Viktor H., East, James E., Morton, Dion, Trusolino, Livio, Maughan, Timothy, Campbell, Andrew D., Loughrey, Maurice B., Dunne, Philip D., Tsantoulis, Petros, Huels, David J., Tejpar, Sabine, Sansom, Owen J., Leedham, Simon J.
Format: Article
Language:English
Subjects:
Animals
cell plasticity
colorectal cancer
colorectal neoplasia
Colorectal Neoplasms - pathology
Homeostasis - physiology
Humans
Intestinal Mucosa - metabolism
intestinal polyps
intestinal stem cells
Intestines
Mice
molecular phenotyping
Neoplastic Stem Cells - pathology
Receptors, G-Protein-Coupled - metabolism
stem cells
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, 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 signaling 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. [Display omitted] •Tumors have Lgr5+ve crypt base columnar (CBC) and Lgr5−ve regenerative stem cells (RSCs)•Stem cell admixture can be measured from transcriptional data using the stem cell index•Stem phenotypes vary by genotype and subtype, shifting with cell signaling disruption•Phenotype shifts from selective pressures associate with poor response to chemotherapy Gil Vasquez et al. demonstrate that intestinal tumors contain variable populations of stem cells whose admixture can be assessed using a transcriptional molecular tool—the stem cell index. Tumor stem cell molecular phenotype associated with lesion subtype and cell-intrinsic and extrinsic signaling disruption and shifted responsively to tumor selective pressures.
ISSN:1934-5909
1875-9777
1875-9777
DOI:10.1016/j.stem.2022.07.008