Spatial constraints govern competition of mutant clones in human epidermis

Abstract

Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

“…Given cancer’s heterogeneous nature (Marusyk et al, 2012), cell competition and cell extrusion are expected to play important roles. Indeed, cell competition by itself has been linked to human tumorigenesis: human cancer cell lines undergo Myc-based cell competition (Di Giacomo et al, 2017), and cell competition was proposed to explain human skin cancer size and mutational distribution (Lynch et al, 2017). Moreover, in mice, Notch-inhibited esophageal progenitor cells outcompete neighboring cells through cell divisions favoring winner renewal and loser differentiation (Alcolea et al, 2014).…”

Cell competition: the winners and losers of fitness selection

“…Similarly, computational data have been used to demonstrate that compensation of cell number following elimination of mutant clones in the Drosophila intestine occurs through increased proliferation of surviving intestinal stem cells (Kolahgar et al, 2015). Finally, mathematical and computational modelling has provided insight into the role of cell competition in promoting the growth of mutant clones in non-diseased human tissue (Lynch et al, 2017). Going forward, such multi-disciplinary approaches are likely to be fruitful for understanding cell dynamics in a broader range of cell competition contexts.…”

“…It is clear from Drosophila studies that cell competition promotes expansion of oncogenic clones (Eichenlaub et al, 2016;Suijkerbuijk et al, 2016). Furthermore, the expansion of mutant clones in human skin is suggestive that competition mechanisms promote the selection of fitter clones (Lynch et al, 2017;Martincorena et al, 2015). However, it is still unclear whether this expansion in human tissues is fuelled by death of wild-type cells, as happens in Drosophila (Li and Baker, 2007), or occurs through more subtle mechanisms such as differences in stem cell self-renewal.…”

Epidermal Darwinism and Competitive Equilibrium within the Epidermis

“…Here, two new studies in this issue of Cell Stem Cell from the groups of Valentina Greco (Mesa et al, 2018) and Phil Jones (Murai et al, 2018), together with other studies (Deschene et al, 2014;Lynch et al, 2017), provide insights into this question and reveal competition within the epidermis. Mesa et al (2018) used intravital imaging to study the plantar skin of transgenic mice with membrane or nuclear labeling.…”