How Do Cells Adapt? Stories Told in Landscapes

Abstract

Cells adapt to changing environments. Perturb a cell and it returns to a point of homeostasis. Perturb a population and it evolves toward a fitness peak. We review quantitative models of the forces of adaptation and their visualizations on landscapes. While some adaptations result from single mutations or few-gene effects, others are more cooperative, more delocalized in the genome, and more universal and physical. For example, homeostasis and evolution depend on protein folding and aggregation, energy and protein production, protein diffusion, molecular motor speeds and efficiencies, and protein expression levels. Models provide a way to learn about the fitness of cells and cell populations by making and testing hypotheses.

Heterozygous transcriptional signatures unmask variable premature termination codon (PTC) burden alongside pathway-specific adaptations in blood outgrowth endothelial cells from patients with nonsense DNA variants causing hereditary hemorrhagic telangiectasia

“…78, 79 In particular, whether inefficient NMD in the setting of persistent, highly expressed nonsense-derived proteins compromises cellular ability to respond to exogenous stresses will need to be the subject of further experimental studies based on preselected genotypes since in the non-selected GTEx tissues, MAFs were too low to obtain genome-wide significant p values for expression QTLs. Notably, the findings are in keeping with longstanding 80 and more recent 81–83 evidence that cellular resource-favourable adaptations of downregulation are more likely to be selected over lifetimes than upregulations which commonly characterise acute responses to maintain homeostasis, as seen for iron in the current and earlier studies. 33 The findings also highlight that for inherited diseases, cellular transcriptional profiles (and responses to exogenous stressors), are likely to differ if deleterious variants generate proteins that are present but require degradation in the endoplasmic reticulum (e.g.…”

“…Notably, the findings are in keeping with longstanding 80 and more recent [81][82][83] evidence that cellular resource-favourable adaptations of downregulation are more likely to be selected over lifetimes than upregulations which commonly characterise acute responses to maintain homeostasis, as seen for iron in the current and earlier studies. 33 The findings also highlight that for inherited diseases, cellular transcriptional profiles (and responses to exogenous stressors), are likely to differ if deleterious variants generate proteins that are present but require degradation in the endoplasmic reticulum (e.g.…”

Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma

“…Thus, a tumor may contain cells belonging to different “attractors” in various time-dependent and space-dependent proportions ( Yeo and Guan, 2017 ; Wouters et al., 2020 ). Quantifying corresponding cell-state transitions and their landscapes is thus essential for a better understanding of diverse adaptive strategies cancer cells can take ( Jia et al., 2017 ; Agozzino et al., 2020 ).…”

Cancer: More Than a Geneticist’s Pandora’s Box

“…These conditions are akin to conditions imposed by energy minimization principles during protein folding, such that only a limited number of protein configurations are achieved, starting from a given amino acid sequence. Thus, cells can be postulated to traverse in a landscape where each "attractor" corresponds to stable phenotypes and has a specific basin of attraction (Agozzino et al, 2020). During cancer progression, various genomic changes may alter access to various cell types/attractors, thus modifying the underlying landscape (Huang et al, 2009).…”