Biology subjects

Devanny, A. J.

Publications and source records attributed to Devanny, A. J..

3 recordsLinked to original sources

bioRxiv2024

Density-based optimization for unbiased, reproducible clustering applied to single molecule localization microscopy

Single molecule localization microscopy (SMLM) has provided insight into the spatial organization of molecules at length scales below the diffraction limit of visible light. In SMLM data, density-based clustering approaches have proven to be valuable tools for probing the nanoscale structure of biological molecules, although little guidance is available for evaluating the accuracy of these results, which are often strongly dependent on user-input parameters. Here, we develop an efficient implementation of density-based cluster validation (DBCV) that can quantitatively evaluate clustering performance in SMLM-sized datasets without ground truth knowledge. We demonstrate that maximizing DBCV scores accurately identifies ground truth clustering in noisy, simulated datasets. By coupling DBCV score maximization with Bayesian optimization, we outline an optimization method, DBOpt, that selects unbiased input parameters for density-based clustering algorithms. We demonstrate that optimal input parameters can be selected for popular algorithms (DBSCAN, HDBSCAN, OPTICS) with minimal user input. Lastly, we show that DBOpt reports accurate feature sizes in 2D and 3D experimental datasets. Taken together, we propose an analysis pipeline that can be applied to a diverse array of experimental data that will improve the integrity and quality of cluster analyses in the broader scientific community.

biophysics↗

bioRxiv2024

Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling.

Certain mutations can confer neomorphic gain of function (GOF) activities to the p53 protein that affect cancer progression. Yet the concept of mutant p53 GOF has been challenged. Here, using various strategies to alter the status of mutant versions of p53 in different cell lines, we demonstrate that mutant p53 stimulates cancer cell invasion in three-dimensional environments. Mechanistically, mutant p53 enhances RhoA/ROCK-dependent cell contractility and cell-mediated extracellular matrix (ECM) re-organization via increasing mevalonate pathway-dependent RhoA localization to the membrane. In line with this, RhoA-dependent pro-invasive activity is also mediated by IDI-1, a mevalonate pathway product. Further, the invasion-enhancing effect of mutant p53 is dictated by the biomechanical properties of the surrounding ECM, thereby adding a cell-independent layer of regulation to mutant p53 GOF activity that is mediated by dynamic reciprocal cell-ECM interactions. Together our findings link mutant p53 metabolic GOF activity with an invasive cellular phenotype in physiologically relevant and context-dependent settings. SignificanceThis study addresses the contribution of mutant p53 to the process of cancer cell dissemination in physiologically relevant three-dimensional environments - a key characteristic of metastatic disease. Several mutant p53 proteins display pro-oncogenic activity with respect to cancer cell invasion in 3D environments via mevalonate pathway-dependent Rho/ROCK signaling axis.

cancer biology↗

bioRxiv2023

Signatures of Jamming in the Cellular Potts Model

We explore the jamming transition in the Cellular Potts Model (CPM) as a function of confinement, cell adhesion, and cell shape. To accurately characterize jamming, we compare Potts simulations of unconfined single cells, cellular aggregates, and confluent monolayers as a function of cell adhesion energies and target cell shape. We consider metrics that may identify signatures of the jamming transition, including diffusion coefficients, anomalous diffusion exponents, cell shape, cell-cell rearrangements, and velocity correlations. We find that the onset of jamming coincides with an abrupt drop in cell mobility, rapid transition to sub-diffusive behavior, and cessation of rearrangements between neighboring cells that is unique to confluent monolayers. Velocity correlations reveal collective migration as a natural consequence of high energy barriers to neighbor rearrangements for certain cell types. Cell shapes across the jamming transition in the Potts model are found to be generally consistent with predictions of vertex-type simulations and trends from experiment. Finally, we demonstrate that changes in cell shape can fluidize cellular monolayers at cellular interaction energies where jamming otherwise occurs.

biophysics↗