Speaker
Description
The dynamics and geometry of intestinal crypts have been revealed as a key factor in the regulation of stem cell numbers in homeostasis, defining a framework in which cells compete for colonization of the organ in a neutral way \cite{1,2}. A key question is whether these same principles extend to pathological conditions where neutrality is broken by malignant clones. To address this, we build on the Stochastic Conveyor Belt (SCB) theory \cite{2,3}, whose main parameters are the rate of continuous stem cell divisions, the rate at which stochastic relocations to all directions with neighboring cells occur, and the geometry of the organ.We studied the effect of the breakdown of neutral competition among stem cells by introducing mutant cells with a higher division rate at the start, both experimentally and theoretically. Interestingly, gene expression analysis showed up-regulation of an antigen presentation pathway in those mutant clones, indicating the involvement of the immune system in maintaining neutrality in the stem cell competition. Disruption of antigen presentation machinery or immune cell depletion further accelerated mutant clone fixation, suggesting the immune microenvironment's role in suppressing oncogenic stem cell expansion. Our results show that while specific mutations confer a selective advantage to mutant clones, the majority are stochastically removed. However, an increased immune response is observed in the presence of these mutant clones, which may prevent the fixation of oncogenic clones in the colon. This finding potentially provides a new starting point for future research into immune preventive strategies that support the elimination of such clones.
Bibliography
@article{1,
author = {Lopez-Garcia, Carlos and Klein, Allon M. and Simons, Benjamin D. and Winton, Douglas J.},
title = {Intestinal Stem Cell Replacement Follows a Pattern of Neutral Drift},
journal = {Science},
year = {2010},
volume = {330},
pages = {822--825},
doi = {10.1126/science.1196236}
}
@article{2,
author = {Azkanaz, Maria and Corominas-Murtra, Bernat and Ellenbroek, Saskia I. J. and Bruens, Lotte and Webb, Anna T. and Laskaris, Dimitrios and Oost, Koen C. and Lafirenze, Simona J. A. and Annusver, Karl and Messal, Hendrik A. and Iqbal, Sharif and Flanagan, Dustin J. and Huels, David J. and Rojas-Rodríguez, Felipe and Vizoso, Miguel and Kasper, Maria and Sansom, Owen J. and Snippert, Hugo J. and Liberali, Prisca and Simons, Benjamin D. and Katajisto, Pekka and Hannezo, Edouard and van Rheenen, Jacco},
title = {Retrograde Movements Determine Effective Stem Cell Numbers in the Intestine},
journal = {Nature},
year = {2022},
volume = {607},
pages = {548--554},
doi = {10.1038/s41586-022-04962-0}
}
@article{3,
author = {Corominas-Murtra, Bernat and Scheele, Colinda L. G. J. and Kishi, Kasumi and Ellenbroek, Saskia I. J. and Simons, Benjamin D. and van Rheenen, Jacco and Hannezo, Edouard},
title = {Stem Cell Lineage Survival as a Noisy Competition for Niche Access},
journal = {Proceedings of the National Academy of Sciences},
year = {2020},
volume = {117},
pages = {16969--16975},
doi = {10.1073/pnas.1921205117}
}
