Biology subjects

Prasanna, C. V. S.

Publications and source records attributed to Prasanna, C. V. S..

3 recordsLinked to original sources

bioRxiv2025

Multiscale modeling predicts dependence of mesenchymally transitioned tumor niche fitness on cell-cell and cell-matrix adhesions

Invasion of cancer cells is often characterized by a transition in phenotype of cells or their niches from an epithelial to a mesenchymal state (EMT). Under what conditions do transitioned niches acquire greater fitness than, and outcompete, their parental un-transitioned niches, is not well-understood. Here, we use a Cellular Potts model-based multiscale computational framework to investigate this question. Inducing an EMT in a single cell at the edge of an early-growing tumor surrounded by a fibrillar extracellular matrix (ECM) allows us to temporally trace inter-niche competitions. We observe that the transitioned niche dominates the population it arises from and invades better when surrounded by dense ECM. An increase in cell-ECM adhesion by itself drives domination at 50% probability, such that the transitioned population invades faster and contributes further to collective invasion of the whole tumor. Decrease in inter- and intra-niche cell-cell adhesion by itself is not sufficient to achieve domination. However, added to increased cell-ECM adhesion, loss of intra-niche (but not inter-niche adhesion) restores the probability, but not the extent, with which domination by the transitioned niche is achieved by attenuating its confinement by its parental population. Our simulations reveal the forces regulating such confinement and how cell-cell and cell-ECM adhesion, stochastic invasion dynamics, and ECM density contribute nuancedly to distinct aspects of inter-niche competitions within tumor populations and their fitness.

cancer biology↗

bioRxiv2024

Dicarbonyl stress debilitates mesothelial defense against metastasizing ovarian cancer

Chronic metabolic disorders and aging result in accumulation of active dicarbonyls that glycate biomolecules rendering them dysfunctional. Although metabolic aberrations are known to be epidemiologically associated with faster cancer progression, cell biological determinants of such associations remain elusive. The formation of micro-metastases in epithelial ovarian cancer involves its colonization of visceral peritonea through clearance of mesothelia that line the coelom. In this study, we observe that cocultures of immortalized human coelomic MeT-5A mesothelia with human ovarian cancer cells OVCAR-3 and SK-OV-3 show greater infiltration by the latter when exposed to increasing concentrations of the dicarbonyl methylglyoxal (MG). Treatment with increasing concentrations of MG caused death and senescence within human and murine serosal mesothelia. Cells showed higher levels of advanced glycation end products, dysregulated occludens junction protein ZO-1, and disrupted localization of cortical filamentous actin and its regulator ezrin, indicating poor inter-cell adhesion. Time lapse imaging also showed impaired migration for MG-treated single mesothelia and for their collective monolayers. Agent-based computer modeling of coculture dynamics predicted that a combined effect of confluence and migration allows inter-adherent mesothelia to contain the spread of colonizing cancer cells, which was confirmed through coculture time lapses of cancer colonization within higher and lower mesothelial densities. We found ovarian cancer cells showed higher levels of glyoxalase-1 (GLO-1) enzyme, which catabolizes MG, suggesting how they escaped its cytotoxic effects. Consistent with this, treatment of OVCAR-3 with MG concurrently with pharmacological inhibition of GLO-1 showed greater cell death. Our results suggest dicarbonyl stress helps colonizing cancer cells overcome the resistance of natural homoeostatic barriers and its inhibition may, in supplementation with chemotherapy, stem metastasis.

cancer biology↗

bioRxiv2023

Spatial heterogeneity in tumor adhesion qualifies collective cell migration

Collective cell migration, a canon of most invasive solid tumors, is an emergent property of the interactions between cancer cells and their surrounding extracellular matrix (ECM). However, tumor populations invariably consist of cells expressing variable levels of adhesive proteins that mediate such interactions, disallowing an intuitive understanding of how tumor invasiveness at a multicellular scale is influenced by spatial heterogeneity of cell-cell and cell-ECM adhesion. Here, we have used a Cellular Potts model-based multiscale computational framework that is constructed on the histopathological principles of glandular cancers. In earlier efforts on homogenous cancer cell populations, this framework revealed the relative ranges of interactions, including cell-cell and cell-ECM adhesion that drove collective, dispersed, and mixed multimodal migrations. Here, we constitute a tumor core of two separate cell subsets showing distinct intra-subset cell-cell or cell-ECM adhesion strengths. These two subsets of cells are arranged to varying extents of spatial intermingling, which we call the heterogeneity index (HI). Our simulations show that for a given two intra-subset cell-cell adhesions for two subsets of cells, low and high inter-subset cell adhesion favors migration of high HI and low HI intermingled populations, respectively. In addition, for the most explored values of cell-ECM adhesion strengths, populations with high HI values collectively migrate better than those with lower HI values. We then asked how spatial migration is regulated by progressively intermingled cellular subsets that were epithelial, i.e., showed high cell-cell but poor cell-ECM adhesion, and mesenchymal, i.e., with reversed adhesion strengths to the former. Here too, inter-subset adhesion plays an important role in contextualizing the proportionate relationship between HI and migration. We also observe an exception to this relationship for cases of heterogeneous cell-ECM adhesion where sub-maximal HI patterns with higher outer localization of cells with stronger ECM adhesion collectively migrate better than their relatively higher HI counterparts. Our simulations also reveal how adhesion heterogeneity qualifies migrative dynamics through collective cellular unjamming, when either cell-cell or -ECM adhesion type is varied but incorporates dispersion when both adhesion types are simultaneously altered.

systems biology↗