Biology subjects

Sadhu, G.

Publications and source records attributed to Sadhu, G..

4 recordsLinked to original sources

bioRxiv2026

A mathematical investigation of the interplay between vasculature and intratumoral cellular heterogeneity during tumor progression

Tumors consist of heterogeneous phenotypic cells, such as normoxic cells, which are highly proliferative, and hypoxic cells, which are less proliferative. Their phenotypic switching depends on tumor microenvironmental factors, such as oxygen and nutrient concentrations supplied by local blood vessels. However, during ongoing angiogenesis, the process of sprouting new blood vessels at the tumor site from pre-existing blood vessels, and how this phenotypic switching affects and impacts tumor growth, remains poorly understood. In this article, we formulate a mathematical model to elucidate the crosstalk between vasculature and tumor cellular heterogeneity during tumor progression. The model results show a strong agreement with the experimental data. Our simulation results demonstrate that ongoing angiogenesis increases tumor growth rate. In addition, we observe that the influence of hypoxic cells on phenotypic switching from normoxic to hypoxic is more pronounced than their influence on the transition from hypoxic to normoxic. Furthermore, we perform a global sensitivity analysis using the Sobol's method to assess the importance of the model's parameters. It highlights that the volume at which blood vessels attain half-maximal rate has the maximum effect on the model.

systems biology↗

bioRxiv2026

Traveling Wave Analysis of a Go-or-Grow Invasion Model with ECM-Regulated Phenotypic Switching

Experimental studies show that tumor cells adopt migratory or proliferative phenotypes depending on the local extracellular matrix (ECM). In this work, we propose a minimal go-or-grow invasion model, comprising two specialist cell phenotypes: proliferating and migratory, with phenotypic switching and cell migration depending on local ECM density. Numerical simulations of this model reveal that the spatial arrangement of proliferative and migratory cells depends on the choice of phenotypic switching function. We then ask whether this specialist cell-phenotype model can be reduced to a generalist cell-phenotype model. We derive a relationship between the reduced model and go-or-grow model in the fast phenotypic switching regime. We observe that the reduced model captures the dynamics of the original model, for a range of realistic phenotypic switching functions. We analytically derive the minimum traveling wave speed of the reduced model in a homogeneous ECM bed. Moreover, using linear stability analysis on the go-or-grow model, we recover the same wave speed expression. In addition, we numerically explore how the key parameters influence the traveling wave speed profile. Our analysis indicated the counter-intuitive result that the wave speed is independent of the matrix degradation rate, and our simulations show that, at most, the speed is weakly dependent on this parameter.

systems biology↗

bioRxiv2026

Time-dependent memory of hypoxia exposure influences tumor invasion dynamics

Cancer cells in hypoxic environments often proliferate less but exhibit enhanced migration relative to their normoxic counterparts. Recent in vitro and in silico studies have characterized the role of hypoxic memory - the ability of cancer cells to retain their hypoxic phenotype even when reoxygenated - in tumor invasion. However, the observations have been limited either to exposing cancer cells to hypoxia for a fixed duration or by assuming a fixed-time persistence of the hypoxic state upon reoxygenation independent of the duration of hypoxia exposure. Thus, time-dependent cell-state changes during hypoxia and their impact on hypoxic memory remains unclear. Here, we first analyze transcriptomic data from breast cancer samples to show that the genes upregulated at transcriptional level and hypomethylated at epigenetic level are enriched in cell invasion, indicating hypoxic memory-driven process of tumor invasion. Next, we used a computational model to investigate how the spatial-temporal dynamics of oxygen levels in a tumor drive time-dependent changes in hypoxic memory and influence tumor invasion dynamics. Our simulation results show that such dynamic hypoxic memory can drive enhanced tumor invasion over a fixed hypoxic memory by a) enriching hypoxic cell density at the tumor front, b) reducing sensitivity of hypoxic cell state to fluctuations in oxygen supply, and c) enhancing effective diffusion of hypoxic cells. Our results highlight the crucial role of dynamic hypoxic memory in shaping tumor invasion dynamics, underscoring the need to elucidate its underlying mechanisms in future studies.

systems biology↗

bioRxiv2025

A phenotype-structured PDE framework for investigating the role of hypoxic memory on tumor invasion under cyclic hypoxia

Tumor growth and angiogenesis drive complex spatiotemporal variation in micro-environmental oxygen levels. Previous experimental studies have observed that cancer cells exposed to chronic hypoxia retained a phenotype characterized by enhanced migration and reduced proliferation, even after being shifted to normoxic conditions, a phenomenon which we refer to as hypoxic memory. However, because dynamic hypoxia and related hypoxic memory effects are challenging to measure experimentally, our understanding of their implications in tumor invasion is quite limited. Here, we propose a novel phenotype-structured partial differential equation modeling framework to elucidate the effects of hypoxic memory on tumor invasion along one spatial dimension in a cyclically varying hypoxic environment. We incorporated hypoxic memory by including time-dependent changes in hypoxic-to-normoxic phenotype transition rate upon continued exposure to hypoxic conditions. Our model simulations demonstrate that hypoxic memory significantly enhances tumor invasion without necessarily reducing tumor volume. This enhanced invasion was sensitive to the induction rate of hypoxic memory, but not the dilution rate. Further, shorter periods of cyclic hypoxia contributed to a more heterogeneous profile of hypoxic memory in the population, with the tumor front dominated by hypoxic cells that exhibited stronger memory. Overall, our model highlighted the complex interplay between hypoxic memory and cyclic hypoxia in shaping heterogeneous tumor invasion patterns.

systems biology↗