Aneuploidy, referring to unbalanced chromosome numbers, represents a class of genetic variation associated with cancer, birth defects and eukaryotic microbes 1 – 4 . Whereas it is known that each aneuploid chromosome stoichiometry can give rise to a distinct pattern of gene expression and phenotypic profile 4 , 5 , it has remained a fundamental question as to whether there are common cellular defects associated with aneuploidy. In this study, we designed a unique strategy that allowed for the observation of common transcriptome changes of aneuploidy by averaging out karyotype-specific dosage effects using aneuploid yeast cell populations with random and diverse chromosome stoichiometry. This analysis uncovered a common aneuploidy gene-expression (CAGE) signature suggestive of hypo-osmotic stress. Consistently, aneuploid yeast exhibited increased plasma membrane (PM) stress leading to impaired endocytosis, and this defect was also observed in aneuploid human cells. Thermodynamic modeling showed that hypo-osmotic-like stress is a general outcome of proteome imbalance caused by aneuploidy and predicted a ploidy-cell size relationship observed in yeast and aneuploid cancer cells. A genome-wide screen further uncovered a general dependency of aneuploid cells on a pathway of ubiquitin-mediated endocytic recycling of nutrient transporters. Loss of this pathway coupled with the aneuploidy-inherent endocytic defect leads to marked alteration of intracellular nutrient homeostasis.

The ability of cells to sense and respond to mechanical cues from the surrounding environment has been implicated as a key regulator of cell differentiation, migration, and proliferation. The extracellular matrix (ECM) is an oft-overlooked component of the interface between cells and their surroundings. Cells assemble soluble ECM proteins into insoluble fibrils with unique mechanical properties that can alter the mechanical cues a cell receives. In this study, we construct a model that predicts the dynamics of cellular traction force generation and subsequent assembly of fibrils of the ECM protein fibronectin (FN). FN fibrils are the primary component in primordial ECM and, as such, FN assembly is a critical component in the cellular mechanical response. The model consists of a network of Hookean springs, each representing an extensible domain within an assembling FN fibril. As actomyosin forces stretch the spring network, simulations predict the resulting traction force and FN fibril formation. The model accurately predicts FN fibril morphometry and demonstrates a mechanism by which FN fibril assembly regulates traction force dynamics in response to mechanical stimuli and varying surrounding substrate stiffness.

Cells respond to mechanical cues from the substrate to which they are attached. These mechanical cues drive cell migration, proliferation, differentiation, and survival. Previous studies have highlighted three specific mechanisms through which substrate stiffness directly alters cell function: increasing stiffness drives 1) larger contractile forces; 2) increased cell spreading and size; and 3) altered nuclear deformation. While studies have shown that substrate mechanics are an important cue, the role of the extracellular matrix (ECM) has largely been ignored. The ECM is a crucial component of the mechanosensing system for two reasons: 1) many ECM fibrils are assembled by application of cell-generated forces, and 2) ECM proteins have unique mechanical properties that will undoubtedly alter the local stiffness sensed by a cell. We specifically focused on the role of the ECM protein fibronectin (FN), which plays a critical role in de novo tissue production. In this study, we first measured the effects of substrate stiffness on human embryonic fibroblasts by plating cells onto microfabricated pillar arrays (MPAs) of varying stiffness. Cells responded to increasing substrate stiffness by generating larger forces, spreading to larger sizes, and altering nuclear geometry. These cells also assembled FN fibrils across all stiffnesses, with optimal assembly occurring at approximately 6 kPa. We then inhibited FN assembly, which resulted in dramatic reductions in contractile force generation, cell spreading, and nuclear geometry across all stiffnesses. These findings suggest that FN fibrils play a critical role in facilitating cellular responses to substrate stiffness.

High-grade gliomas are especially difficult tumors to treat due to their invasive behavior. This has led to extensive research focusing on arresting glioma cell migration. Cell migration involves the sensing of a migratory cue, followed by polarization in the direction of the cue, and reorganization of the actin cytoskeleton to allow for a protrusive leading edge and a contractile trailing edge. Transmission of these forces to produce motility also requires adhesive interactions of the cell with the extracellular microenvironment. In glioma cells, transmembrane receptors such as CD44 and integrins bind the cell to the surrounding extracellular matrix that provides a substrate on which the cell can exert the requisite forces for cell motility. These various essential parts of the migratory machinery are potential targets to halt glioma cell invasion. In this review, we discuss the mechanisms of glioma cell migration and how they may be targeted in anti-invasion therapies.