Seminars

Stochastic search is ubiquitous in biology and ecology, from synaptic transmission and intracellular signaling to predators seeking prey and the spread of disease. In dynamic systems like these, the number of 'searchers' is rarely constant: new agents may be recruited while others can abandon the search. Despite the ubiquity of these dynamics, their combined influence on search times remains largely unexplored. In this talk we will introduce a general framework for stochastic search in which agents progressively join and leave the process, a mechanism we term 'dynamic redundancy and mortality'. Under minimal assumptions on the underlying search dynamics, our framework yields the exact distribution of the first-passage time to a target region and further reveals surprising connections to stochastic search with stochastic resetting, wherein a single searcher is randomly 'reset' to its initial state. We will then treat the target region as a queue, which we show has interarrival times governed by a thinned nonhomogeneous Poisson process. Altogether this work provides a rigorous foundation for studying stochastic search processes with a fluctuating number of searchers. This work is in collaboration with Dr. Aanjaneya Kumar (Santa Fe Institute) and José Giral-Barajas (Imperial College London).

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.

Keywords: Tumor invasion, cyclic hypoxia, hypoxic memory, phenotype-structured model