Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Vasquez, Ester Gil; Nasreddin, Nadia; Valbuena, Gabriel N; Mulholland, Eoghan J; Belnoue-Davis, Hayley L; Eggington, Holly R; Schenck, Ryan O; Wouters, Valerie M; Wirapati, Pratyaksha; Gilroy, Kathryn; Lannagan, Tamsin RM; Flanagan, Dustin J; Najumudeen, Arafath K; Omwenga, Sulochana; McCorry, Amy MB; 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

doi:10.1016/j.stem.2022.07.008

Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Author:

Vasquez, Ester Gil

Nasreddin, Nadia ; Valbuena, Gabriel N ; Mulholland, Eoghan J ; Belnoue-Davis, Hayley L ; Eggington, Holly R ; Schenck, Ryan O ; Wouters, Valerie M ; Wirapati, Pratyaksha ; Gilroy, Kathryn ; Lannagan, Tamsin RM ; Flanagan, Dustin J ; Najumudeen, Arafath K ; Omwenga, Sulochana ; McCorry, Amy MB ; 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

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell & Tissue Engineering, Cell Biology, SMALL-INTESTINE, IN-VITRO, EXPRESSION, COLON, MICROENVIRONMENT, IDENTIFICATION, TUMORIGENESIS, METASTASIS, PLASTICITY, SIGNATURES, cell plasticity, colorectal cancer, colorectal neoplasia, intestinal polyps, intestinal stem cells, molecular phenotyping, stem cells, Animals, Colorectal Neoplasms, Homeostasis, Humans, Intestinal Mucosa, Intestines, Mice, Neoplastic Stem Cells, Receptors, G-Protein-Coupled, PROGRAM, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences, 32 Biomedical and clinical sciences

Abstract:

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.