Collective motion conceals fitness differences in crowded cellular populations

Abstract

Many cellular populations are tightlypacked, for example microbial colonies and biofilms [39,10,41], or tissues and tumors in multi-cellular organisms [11,29]. Movement of one cell inside such crowded assemblages requires movement of others, so that cell displacements are correlated over many cell diameters [28,6,31]. Whenever movement is important for survival or growth [15,34,38,9], such correlated rearrangements could couple the evolutionary fate of di↵erent lineages. Yet, little is known about the interplay between mechanical stresses and evolution in dense cellular populations. Here, by tracking deleterious mutations at the expanding edge of yeast colonies, we show that crowding-induced collective motion prevents costly mutations from being weeded out rapidly. Joint pushing by neighboring cells generates correlated movements that suppress the di↵erential displacements required for selection to act. Such mechanical screening of fitness di↵erences allows the mutants to leave more descendants than expected under non-mechanical models, thereby increasing their chance for evolutionary rescue [2,5]. Our work suggests that mechanical interactions generally influ-ence evolutionary outcomes in crowded cellular populations, which has to be considered when modeling drug resistance or cancer evolution [1,22,34,30,36,42]. As a model system for crowded cellular populations, we focused on colonies of the budding yeast Saccharomyces cerevisiae [33]. Since yeast cells lack motility, colony expansion is fueled purely by the pushing forces generated by cellular growth and division [14,7]. To explore how these pushing forces a↵ect the strength of natural selection, we competed "mutant" cells, carrying a growth-rate deficit, with faster-growing "wild-type" cells in expanding colonies (Fig. 1a-c). Mutant and wild-type cells remained in well-segregated sectors during the expansion [15], which allowed us to use time-resolved fluorescence microscopy to monitor the gradual demise of the mutant fraction. We then measured the rate at which mutant cells are out-competed by faster-growing wildtype cells at the expanding front of a linear colony (Fig. 1c).We found that mutants were weeded out from the expanding frontier in two main stages. In the first stage, the width of mutant sectors decreased at a constant rate. This is in line with a minimal model where local front expansion velocities depend only on the cell-type specific growth rates of the "pioneer" 1

Spatial organization in microbial range expansion emerges from trophic dependencies and successful lineages

“…The shape of the emerging super sector has previously been linked to the relative growth rate advantages 35 . Similar observations have been made in studies focusing on the mechanical forces shaping the spatial patterns of mutant strains with relative growth rate differences during range expansion 17,18 . In both cases, cells having a growth rate disadvantage managed to stay at the colony periphery through mechanical interactions, and shoving of the surrounding faster growing cells.…”

“…Within such highly constrained systems, scenarios emerge in which a few cells contribute disproportionally to the long term community biomass 10 supporting the notion of "survival of the luckiest". Evidence in the form of genetic segregation of initially mixed communities is observed frequently in colonies growing on surfaces [11][12][13][14][15][16][17][18] , or observations of detrimental mutations accumulating at the assemblage periphery that are rapidly lost in homogeneous environments such as liquid cultures 19 . During sessile growth, bacterial cells are essentially fixed in space and depend on diffusional fluxes dictated by heterogeneous nutrient landscapes (governed by the surface and their neighbors) that ultimately shape the resulting bacterial assemblage 6 .…”

Physical interactions reduce the power of natural selection in growing yeast colonies

“…They showed that the probability that a mutant spreads in the population can be related to summary statistics characterizing cell alignment and the front roughness. In parallel to our investigation, Kayser et al ( 19 ) showed that the mechanical interaction between a faster-growing and a slower-growing strain can cause the prolonged survival of the slower-growing one at the colony frontier, a process that we have investigated in a different geometry and from a different modeling perspective.…”

Probing the Functional Role of Physical Motion in Development

“…Of particular interest may be methods for an enhanced characterization of jamming and folding in developing tissues (Mongera et al, 2018;Nnetu et al, 2012;Petridou et al, 2019;Trushko et al, 2018). Furthermore, flow perturbations could be used to mimic tissue-jamming dynamics with cellular systems of reduced complexity (Kayser et al, 2018). Also, highly advantageous would be physical methods to enhance the transport of metabolites and waste products within 3D tissue cultures.…”