Titrating CD47 by mismatch CRISPR-interference reveals incomplete repression can eliminate IgG-opsonized tumors but limits induction of antitumor IgG

Phagocytic elimination of solid tumors by innate immune cells seems attractive for immunotherapy, particularly because of the possibilities for acquired immunity. However, the approach remains challenging, with blockade of the macrophage checkpoint CD47 working in immunodeficient mice and against highly immunogenic tumors but not in the clinic where tumors are poorly immunogenic. Even when mouse … Read more

Confinement plus Myosin-II suppression maximizes heritable loss of chromosomes, as revealed by live-cell ChReporters

The mechanical environment of a cell can have many effects, but whether it impacts the DNA sequence of a cell has remained unexamined. To investigate this, we developed a live-cell method to measure changes in chromosome numbers. We edited constitutive genes with GFP or RFP tags on single alleles and discovered that cells that lose … Read more

Genetic heterogeneity in p53-null leukemia increases transiently with spindle assembly checkpoint inhibition and is not rescued by p53

Chromosome gains or losses often lead to copy number variations (CNV) and loss of heterozygosity (LOH). Both quantities are low in hematologic “liquid” cancers versus solid tumors in data of The Cancer Genome Atlas (TCGA) that also shows the fraction of a genome affected by LOH is ~ one-half of that with CNV. Suspension cultures of p53-null … Read more

Small lipid droplets are rigid enough to indent a nucleus, dilute the lamina, and cause rupture

The nucleus in many cell types is a stiff organelle, but fat-filled lipid droplets (FDs) in cytoplasm are seen to indent and displace the nucleus. FDs are phase-separated liquids with a poorly understood interfacial tension γ that determines how FDs interact with other organelles. Here, micron-sized FDs remain spherical as they indent peri-nuclear actomyosin and … Read more

Tension-suppressed degradation of collagen controls tissue stiffness scaling with fibrillar collagen

Extremely soft tissues such as developing hearts or adult brain contain far less collagen than highly stiff adult tissues such as tendons, but cell and molecular mechanisms for such homeostatic differences remain unclear. We hypothesized that cell-generated or exogenous forces combine with tension-suppressed collagen degradation in order to sculpt extracellular matrix (ECM) collagen levels in … Read more

Matrix Elasticity Directs Stem Cell Lineage Specification

Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, … Read more