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