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• W2051257436 abstract "Have you seen?1 September 2014free access Stem cell competition: how speeding mutants beat the rest Edward R Morrissey Edward R Morrissey Cancer Research UK – Cambridge Institute, University of Cambridge, Cambridge, UK Search for more papers by this author Louis Vermeulen Louis Vermeulen [email protected] Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands Search for more papers by this author Edward R Morrissey Edward R Morrissey Cancer Research UK – Cambridge Institute, University of Cambridge, Cambridge, UK Search for more papers by this author Louis Vermeulen Louis Vermeulen [email protected] Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands Search for more papers by this author Author Information Edward R Morrissey1 and Louis Vermeulen2 1Cancer Research UK – Cambridge Institute, University of Cambridge, Cambridge, UK 2Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands The EMBO Journal (2014)33:2277-2278https://doi.org/10.15252/embj.201489823 See also: M Amoyel et al (October 2014) and AM Baker et al (August 2014) PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info How mutations lead to tumor formation is a central question in cancer research. Although cellular changes that follow the occurrence of common mutations are well characterized, much less is known about their effects on the population level. Now, two recent studies reveal in what way oncogenic aberrations alter stem cell dynamics to provide cells with an evolutionary advantage over their neighbors (Amoyel et al, 2014; Baker et al, 2014). In most tissues, stem cells not only face the continuous demand of generating sufficient differentiated cells to maintain tissue integrity but also continuously battle each other for a position within the niche. Recent studies have employed quantitative analytical techniques to describe stem cell dynamics in remarkable detail. Strikingly the fundamental properties of these dynamics are universal, although the spatial features of the various tissues might be drastically different (Klein & Simons, 2011). Stem cells are routinely lost following terminal differentiation and replaced by neighboring symmetrically dividing stem cells in a stochastic manner (Fig 1A). In homeostasis, this process results in neutral competition between clones that is characterized by random expansion and retraction of clones (Klein & Simons, 2011). Figure 1. Stem cell dynamics and oncogenic transformation(A) Both fly testis (cyst) stem cells and human ISCs behave in similar fashion. During homeostasis, stem cells continuously compete with their neighbors randomly replacing them or being replaced. (B) Amoyel et al have shown that mutations can confer a competitive advantage by speeding up the mutant stem cell proliferation rate which in turn makes the stem cells more likely to take up vacant niche positions. (C) A potential consequence of this elevated proliferation, once all stem cells are mutant, is the overwhelming of homeostatic control mechanisms leading to higher numbers of stem cells compared to wild type. This would explain the observation by Baker et al for human adenomatous crypts, where the crypts were found to have a larger number of stem cells with an accelerated stem cell replacement rate. Download figure Download PowerPoint Amoyel and colleagues now describe that also somatic cyst stem cells (CySCs) within the Drosophila testis follow neutral stochastic dynamics (Amoyel et al, 2014). Hence, also in this tissue, no long-lived stem cells can be detected that unceasingly produce differentiated cells. Instead, maintenance of an effective cyst cell compartment relies on the functioning of a continuously changing equipotent stem cell population. Furthermore, the authors demonstrate that the expression of marker genes that are associated with the Drosophila CySC compartment importantly overestimate the number of functional stem cells. To model the development of neoplastic outgrowths within the testis signals that are known to modulate CySCs were modified. In particular, inactivation of patched (ptc) resulting in constitutive Hedgehog signaling in CySCs led to rapid expansion of these cells. Intriguingly, although the ptc−/− CySCs displayed a competitive advantage over wild-type CySCc, they were still regularly replaced by wild-type stem cells following stochastic events. Using well-designed experiments, the authors established that the increased proliferation rate of ptc−/− CySCs is solely responsible for the increased competitive fitness of the clone. Increased stem cell proliferation augments the probability that their offspring populates a vacant adjacent niche (Fig 1B). This finding parallels a recent discovery in the intestine and highlights how oncogenic mutations can exploit a chief homeostatic process of random stem cell replacement (Snippert et al, 2014). Until recently, much of our knowledge on stem cell dynamics was derived from genetic clonal tracing studies in model organisms such as Drosophila or mouse (Vermeulen & Snippert, 2014). Although it was generally assumed that dynamics in human tissue are fundamentally similar, the specifics remained largely undefined as evidently transgenic lineage-tracing in humans is unfeasible. Now, the Graham lab has employed an elegant clonal tracing strategy in human intestinal tissue that relies on the stochastic inactivation of cytochrome c oxidase (CCO) by somatic mtDNA mutations that can be visualized using a histochemical assay (Baker et al, 2014). In rare cases, individual colon crypts display both CCO+ and CCO− clones. By analyzing the changes in clone sizes within these polyclonal crypts along the crypt axis in 3D reconstructed images, the authors could temporally track the events occurring in the intestinal stem cell (ISC) compartment (loss of stem cells and expansion of neighboring clones). Using this data in conjunction with a previously developed stochastic population model of ISC dynamics, the authors established the occurrence of neutral competition between human ISCs (Lopez-Garcia et al, 2010). Furthermore, they could infer the presence of a rather limited number of functional stem cells, five to six, within each crypt of the human colon. Surprisingly, these numbers are very similar to the amount of functional stem cells in the murine crypts that are considerably smaller (Kozar et al, 2013). The highlight of the study by Baker et al is the analysis of stem cell dynamics in adenomatous crypts harboring a homozygous inactivation of the intestinal tumor suppressor gene APC. The results showed that these glands contain an expanded number of stem cells that replace each other more rapidly than normal ISCs. Keeping in mind the findings of Amoyel et al, it is tempting to speculate that APC−/− cells divide at a higher rate thereby initially outcompeting other cells and eventually overwhelming the homeostatic balancing mechanisms leading to an increased number of stem cells in mutant crypts (Fig 1C). This model also provides a compelling explanation for the mechanism by which loss of APC provides a previously reported competitive advantage to cells (Vermeulen et al, 2013); APC−/− clones contain an increased proportion of stem cells and as such are more resistant to stochastic loss of stem cells, and in addition, the rapid proliferation allows for efficient colonization of nearby vacant niches. The conclusion, from both studies, that mutant stem cells are still often replaced by neighboring cells, and in fact that oncogenic stem cells replace each other even at an accelerated rate, is encouraging. It implies that a large part of the oncogenic stem cells are destined to be lost and that drugs that promote this feature might form the basis of novel effective therapies and preventive interventions. Acknowledgements LV is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and an AICR grant (14-1164). References Amoyel M, Simons BD, Bach EA (2014) Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo. EMBO J 33: 2295–2313Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Baker AM, Cereser B, Melton S, Fletcher AG, Rodriguez-Justo M, Tadrous PJ, Humphries A, Elia G, McDonald SA, Wright NA, Simons BD, Jansen M, Graham TA (2014) Quantification of crypt and stem cell evolution in the normal and neoplastic human colon. Cell Rep 8: 940–947CrossrefCASPubMedWeb of Science®Google Scholar Klein AM, Simons BD (2011) Universal patterns of stem cell fate in cycling adult tissues. Development 138: 3103–3111CrossrefCASPubMedWeb of Science®Google Scholar Kozar S, Morrissey E, Nicholson AM, van der Heijden M, Zecchini HI, Kemp R, Tavare S, Vermeulen L, Winton DJ (2013) Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas. Cell Stem Cell 13: 626–633CrossrefCASPubMedWeb of Science®Google Scholar Lopez-Garcia C, Klein AM, Simons BD, Winton DJ (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science 330: 822–825CrossrefCASPubMedWeb of Science®Google Scholar Snippert HJ, Schepers AG, van Es JH, Simons BD, Clevers H (2014) Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep 15: 62–69Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Vermeulen L, Morrissey E, van der Heijden M, Nicholson AM, Sottoriva A, Buczacki S, Kemp R, Tavare S, Winton DJ (2013) Defining stem cell dynamics in models of intestinal tumor initiation. Science 342: 995–998CrossrefCASPubMedWeb of Science®Google Scholar Vermeulen L, Snippert HJ (2014) Stem cell dynamics in homeostasis and cancer of the intestine. Nat Rev Cancer 14: 468–480CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 33,Issue 20,16 October 2014Cover: Fairy Prion – “Prions are not only misfolded amyloidogenic proteins but also small birds living far out on the ocean. They feed while “walking” across the water and are extremely difficult to photograph,” says Christian Haass of the Ludwig Maximilian University of Munich, who managed to capture this particular fairy prion just above the water surface. The image was one of the selections of the jury in the 2014 cover contest of The EMBO Journal. If you would like to take part in the 2015 contest with some of your own scientific or non-scientific images, send us a quick email at [email protected], and we will notify you when our new contest opens. Volume 33Issue 2016 October 2014In this issue FiguresReferencesRelatedDetailsLoading ..." @default.
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