Targeting myosin II to alter the disease course of challenging diseases.

In this issue of Cell, Kenchappa et al. and Radnai et al. report the development of selective non-muscle myosin II inhibitors that show therapeutic potential in glioblastoma and methamphetamine use disorder, opening new avenues for targeting cell mechanobiology in challenging diseases.

Complementary cytoskeletal feedback loops control signal transduction excitability and cell polarity.

To navigate complex environments, cells integrate chemical and mechanical cues through dynamic feedback between signaling networks and the cytoskeleton. Using synthetic tools to manipulate cytoskeletal components in Dictyostelium and human neutrophils, we uncover feedback mechanisms that regulate Ras/PI3K signaling and control front- and back-states of the cell. Increased branched actin and actin polymerization enhance Ras/PI3K activity.

Ras-mediated dynamic and biphasic regulation of cell migration.

Ras has traditionally been regarded as a positive regulator and therapeutic target due to its role in cell proliferation, but recent findings indicate a more nuanced role in cell migration, where suppressed Ras activity can unexpectedly promote migration. To clarify this complexity, we systematically modulate Ras activity using various RasGEF and RasGAP proteins and assess their effects on migration dynamics. Leveraging optogenetics, we assess the immediate, nontranscriptional effects of Ras signaling on migration.

Dynamic and Biphasic Regulation of Cell Migration by Ras.

Unlabelled: Ras has traditionally been regarded as a positive regulator and therapeutic target due to its role in cell proliferation, but recent findings indicate a more nuanced role in cell migration, where suppressed Ras activity can unexpectedly promote migration. To clarify this complexity, we systematically modulate Ras activity using various RasGEF and RasGAP proteins and assess their effects on migration dynamics. Leveraging optogenetics, we assess the immediate, non-transcriptional effects of Ras signaling on migration.

A continuum model of mechanosensation based on contractility kit assembly.

The ability of cells to sense and respond to mechanical forces is crucial for navigating their environment and interacting with neighboring cells. Myosin II and cortexillin I form complexes known as contractility kits (CKs) in the cytosol, which facilitate a cytoskeletal response by accumulating locally at the site of inflicted stress. Here, we present a computational model for mechanoresponsiveness in Dictyostelium, analyzing the role of CKs within the mechanoresponsive mechanism grounded in experimentally measured parameters.

Discovery and Quantitative Dissection of Cytokinesis Mechanisms Using Dictyostelium discoideum.

The social amoeba Dictyostelium discoideum is a versatile model for understanding many different cellular processes involving cell motility including chemotaxis, phagocytosis, and cytokinesis. Cytokinesis, in particular, is a model cell-shaped change process in which a cell separates into two daughter cells. D.

Synthetic control of actin polymerization and symmetry breaking in active protocells.

Nonlinear biomolecular interactions on membranes drive membrane remodeling crucial for biological processes including chemotaxis, cytokinesis, and endocytosis. The complexity of biomolecular interactions, their redundancy, and the importance of spatiotemporal context in membrane organization impede understanding of the physical principles governing membrane mechanics. Developing a minimal in vitro system that mimics molecular signaling and membrane remodeling while maintaining physiological fidelity poses a major challenge.

Benefits and challenges of reconstituting the actin cortex.

The cell's ability to change shape is a central feature in many cellular processes, including cytokinesis, motility, migration, and tissue formation. The cell constructs a network of contractile proteins underneath the cell membrane to form the cortex, and the reorganization of these components directly contributes to cellular shape changes. The desire to mimic these cell shape changes to aid in the creation of a synthetic cell has been increasing.

Complementary Cytoskeletal Feedback Loops Control Signal Transduction Excitability and Cell Polarity.

To move through complex environments, cells must constantly integrate chemical and mechanical cues. Signaling networks, such as those comprising Ras and PI3K, transmit chemical cues to the cytoskeleton, but the cytoskeleton must also relay mechanical information back to those signaling systems. Using novel synthetic tools to acutely control specific elements of the cytoskeleton in and neutrophils, we delineate feedback mechanisms that alter the signaling network and promote front- or back-states of the cell membrane and cortex.

Synthetic control of actin polymerization and symmetry breaking in active protocells.

Non-linear biomolecular interactions on the membranes drive membrane remodeling that underlies fundamental biological processes including chemotaxis, cytokinesis, and endocytosis. The multitude of biomolecules, the redundancy in their interactions, and the importance of spatiotemporal context in membrane organization hampers understanding the physical principles governing membrane mechanics. A minimal, in vitro system that models the functional interactions between molecular signaling and membrane remodeling, while remaining faithful to cellular physiology and geometry is powerful yet remains unachieved.

Nonmuscle myosin IIB is a driver of cellular reprogramming.

Nonmuscle myosin IIB (NMIIB) is considered a primary force generator during cell motility. Yet many cell types, including motile cells, do not necessarily express NMIIB. Given the potential of cell engineering for the next wave of technologies, adding back NMIIB could be a strategy for creating supercells with strategically altered cell morphology and motility.

Particle-based model of mechanosensory contractility kit assembly.

Cell shape change processes, such as proliferation, polarization, migration, and cancer metastasis, rely on a dynamic network of macromolecules. The proper function of this network enables mechanosensation, the ability of cells to sense and respond to mechanical cues. Myosin II and cortexillin I, critical elements of the cellular mechanosensory machinery, preassemble in the cytoplasm of Dictyostelium cells into complexes that we have termed contractility kits (CKs).

The lectin Discoidin I acts in the cytoplasm to help assemble the contractile machinery.

Cellular functions, such as division and migration, require cells to undergo robust shape changes. Through their contractility machinery, cells also sense, respond, and adapt to their physical surroundings. In the cytoplasm, the contractility machinery organizes into higher order assemblies termed contractility kits (CKs).

Cancer as a biophysical disease: Targeting the mechanical-adaptability program.

With the number of cancer cases projected to significantly increase over time, researchers are currently exploring "nontraditional" research fields in the pursuit of novel therapeutics. One emerging area that is steadily gathering interest revolves around cellular mechanical machinery. When looking broadly at the physical properties of cancer, it has been debated whether a cancer could be defined as either stiffer or softer across cancer types.

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion.

A mesoscale mechanical model of cellular interactions.

Computational models of cell mechanics allow the precise interrogation of cell shape change. These morphological changes are required for cells to survive in diverse tissue environments. Here, we present a mesoscale mechanical model of cell-substrate interactions using the level set method based on experimentally measured parameters.

Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function.

Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), which is impacted by cigarette smoking and has no therapeutic options. We utilized a high-copy cDNA library genetic selection approach in the amoeba to identify genetic protectors to cigarette smoke. Members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) are protective against cigarette smoke in and human bronchial epithelial cells.

Tools for computational analysis of moving boundary problems in cellular mechanobiology.

A cell's ability to change shape is one of the most fundamental biological processes and is essential for maintaining healthy organisms. When the ability to control shape goes awry, it often results in a diseased system. As such, it is important to understand the mechanisms that allow a cell to sense and respond to its environment so as to maintain cellular shape homeostasis.

The mechanobiome: a goldmine for cancer therapeutics.

Cancer progression is dependent on heightened mechanical adaptation, both for the cells' ability to change shape and to interact with varying mechanical environments. This type of adaptation is dependent on mechanoresponsive proteins that sense and respond to mechanical stress, as well as their regulators. Mechanoresponsive proteins are part of the mechanobiome, which is the larger network that constitutes the cell's mechanical systems that are also highly integrated with many other cellular systems, such as gene expression, metabolism, and signaling.

Why new biology must be uncovered to advance therapeutic strategies for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar tissue (in emphysema) and airway remodeling (leading to chronic bronchitis), which cause difficulties in breathing. It is a growing public health concern with few therapeutic options that can reverse disease progression or mortality. This is in part because current treatments mainly focus on ameliorating symptoms induced by inflammatory pathways as opposed to curing disease.

4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis.

Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and to navigate tissue barriers.

The Unusual Suspects in Cytokinesis: Fitting the Pieces Together.

Cytokinesis is the step of the cell cycle in which the cell must faithfully separate the chromosomes and cytoplasm, yielding two daughter cells. The assembly and contraction of the contractile network is spatially and temporally coupled with the formation of the mitotic spindle to ensure the successful completion of cytokinesis. While decades of studies have elucidated the components of this machinery, the so-called , and their functions, many lines of evidence are pointing to other unexpected proteins and sub-cellular systems as also being involved in cytokinesis.

TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca.

The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4 triggers increased intracellular Ca through a Ca/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca and neurotoxicity in Drosophila and cultured primary mouse neurons.

Helping Scholars Overcome Socioeconomic Barriers to Medical and Biomedical Careers: Creating a Pipeline Initiative.

To achieve their potential in medical and biomedical careers, students (scholars) from under-resourced backgrounds must build sophisticated skills and develop confidence and professionalism. To flourish in an advanced educational system that may be unfamiliar, these scholars also need networks of mentors and role models. These challenges can affect scholars at multiple stages of their education.