Defining Stem Cell Dynamics in Models of Intestinal Tumor Initiation

Vermeulen, Louis; Morrissey, Edward; Heijden, Maartje van der; Nicholson, Anna M.; Sottoriva, Andrea; Buczacki, Simon; Kemp, Richard; Tavaré, Simon; Winton, Douglas J.

doi:10.1126/science.1243148

Cited by 379 publications

(425 citation statements)

References 38 publications

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“…We tested our model and estimated its parameters using ageincidence curves, cancer exome sequences from ∼1,000 tumors in four cancer subtypes, and data on clinical outcomes. Ageincidence curves support our hypothesis that nearly all lesions fail to progress and allowed us to estimate the fitness benefit of a driver as s d ≈ 0.1−0.6, in good agreement with direct experimental measurements (23). Genomics data also affirmed that a damaging effect of a nonsynonymous passenger is 100 times smaller than the effect of a driver, but passengers are 100 times more numerous than drivers.…”

Section: Discussionsupporting

confidence: 80%

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Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland

Mirny

Korolev

2014

Proc. Natl. Acad. Sci. U.S.A.

151

187

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Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations-a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies.

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Section: Discussionsupporting

confidence: 80%

“…For example, μ varies dramatically across cancers (8), whereas estimates of s d range from 0.0001 (4) to 0.58 (23). Hence, we varied each parameter by 1,000-fold (SI Appendix, Table S1) and found that dynamics varied considerably over this range but fell into two broad categories: adaptation (cancer) and extinction (no progression).…”

Section: Significancementioning

confidence: 99%

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland

Mirny

Korolev

2014

Proc. Natl. Acad. Sci. U.S.A.

151

187

View full text Add to dashboard Cite

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“…The KRAS and BRAF oncogenes may also have contrasting effects on cellular hierarchies in the intestine, as oncogenic KRAS in combination with loss of APC can induce ectopic stem cells in the mouse intestine, 46 and KRAS mutations produced cells that favor ISC over TA cell fate and thus spread within individual crypts. 47 In contrast, our results suggest that oncogenic activation of BRAF would support the adoption of TA over ISC cell fate, which would result in preferential exclusion from the stem cell pool and clonal elimination. However, this assumption has not been tested on a clonal basis here.…”

Section: Discussioncontrasting

confidence: 69%

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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Colon cancer cells frequently carry mutations that activate the β-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/β-catenin signals encourage ISC identity, we asked whether β-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3β. Similarly, transgenic expression of stabilized β-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAF V637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/β-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/β-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.

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“…ISCs are constantly dividing and therefore continually accumulating diverse mutations, which can potentially result in competition-driven drift between ISCs. Recent studies have demonstrated that isolated single ISCs with mutations in Kras and Apc are more prone to clonal expansion relative to surrounding WT ISCs (21,22). Here we examine the effects of stochastic loss of TgfβR2 on competition between mutant and WT ISCs.…”

mentioning

confidence: 98%

Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

Fischer

Calabrese

Miller

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Intestinal stem cells (ISCs) are maintained by a niche mechanism, in which multiple ISCs undergo differential fates where a single ISC clone ultimately occupies the niche. Importantly, mutations continually accumulate within ISCs creating a potential competitive niche environment. Here we use single cell lineage tracing following stochastic transforming growth factor β receptor 2 (TgfβR2) mutation to show cell autonomous effects of TgfβR2 loss on ISC clonal dynamics and differentiation. Specifically, TgfβR2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgfβ signaling controls both ISC clone extinction and expansion, independent of proliferation. In addition, TgfβR2 loss in vivo reduced crypt fission, irradiation-induced crypt regeneration, and differentiation toward Paneth cells. Finally, altered Tgfβ signaling in cultured mouse and human enteroids supports further the in vivo data and reveals a critical role for Tgfβ signaling in generating precursor secretory cells. Overall, our data reveal a key role for Tgfβ signaling in regulating ISCs clonal dynamics and differentiation, with implications for cancer, tissue regeneration, and inflammation.T he intestinal epithelium is constantly renewed by proliferating, multipotent, and self-renewing intestinal stem cells (ISCs) (1). There are two main populations of ISCs: (i) a proliferating ISC population that is important for homeostasis of the niche residing below the +4 position and expressing a set of markers [e.g., leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) and Olfm4] and (ii) a quiescent ISC population residing near the +4 position and expressing a different set of markers (e.g., Bmi1 and Hopx) (2). Proliferating ISCs are the workhorses during normal homeostasis and are maintained within the niche by a close relationship with Paneth cells (3) and the stroma (4). The proliferating ISC population can be further divided into a smaller number (4-8) of functional ISCs (5,6

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Defining Stem Cell Dynamics in Models of Intestinal Tumor Initiation

Cited by 379 publications

References 38 publications

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

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