"Patchiness" in mechanical stiffness across a tumor as an early-stage marker for malignancy.

Mechanical phenotyping of tumors, either at an individual cell level or tumor cell population level is gaining traction as a diagnostic tool. However, the extent of diagnostic and prognostic information that can be gained through these measurements is still unclear. In this work, we focus on the heterogeneity in mechanical properties of cells obtained from a single source such as a tissue or tumor as a potential novel biomarker. We believe that this heterogeneity is a conventionally overlooked source of information in mechanical phenotyping data. We use mechanics-based in-silico models of cell-cell interactions and cell population dynamics within 3D environments to probe how heterogeneity in cell mechanics drives tissue and tumor dynamics. Our simulations show that the initial heterogeneity in the mechanical properties of individual cells and the arrangement of these heterogenous sub-populations within the environment can dictate overall cell population dynamics and cause a shift towards the growth of malignant cell phenotypes within healthy tissue environments. The overall heterogeneity in the cellular mechanotype and their spatial distributions is quantified by a "patchiness" index, which is the ratio of the global to local heterogeneity in cell populations. We observe that there exists a threshold value of the patchiness index beyond which an overall healthy population of cells will show a steady shift towards a more malignant phenotype. Based on these results, we propose that the "patchiness" of a tumor or tissue sample, can be an early indicator for malignant transformation and cancer occurrence in benign tumors or healthy tissues. Additionally, we suggest that tissue patchiness, measured either by biochemical or biophysical markers, can become an important metric in predicting tissue health and disease likelihood just as landscape patchiness is an important metric in ecology.

Differences in cell death and division rules can alter tissue rigidity and fluidization.

Tissue mechanical properties such as rigidity and fluidity, and changes in these properties driven by jamming-unjamming transitions (UJT), have come under recent highlight as mechanical markers of health and disease in various biological processes including cancer. However, most analyses of these mechanical properties and UJT have sidestepped the effect of cellular death and division in these systems. Cellular apoptosis (programmed cell death) and mitosis (cell division) can drive significant changes in tissue properties. The balance between the two is crucial in maintaining tissue function, and an imbalance between the two is seen in situations such as cancer progression, wound healing and necrosis. In this work we investigate the impact of cell death and division on tissue mechanical properties, by incorporating specific mechanosensitive triggers of cell death and division based on the size and geometry of the cell within in silico models of tissue dynamics. Specifically, we look at cell migration, tissue response to external stress, tissue extrusion propensity and self-organization of different cell types within the tissue, as a function of cell death and division and the rules that trigger these events. We find that not only do cell death and division events significantly alter tissue mechanics when compared to systems without these events, but that the choice of triggers driving these cell death and division events also alters the predicted tissue mechanics and overall system behavior.