Presentation Information
[SS22-08]The storage effect enhances cancer cell heterogeneity and evolvability under environmental fluctuations
*Joon-Hyun Song1, David Basanta2, Mehdi Damaghi1 (1. Stony Brook University (United States of America), 2. Moffitt Cancer Center (United States of America))
Keywords:
Cancer evolution,Heterogeneity,Temporal fluctuation,Storage effect,Agent-Based Modelling
Tumor heterogeneity critically influences tumor evolution and treatment outcomes. While increased mutational burden has traditionally been considered a significant contributor to heterogeneity, phenotypic diversity often emerges independently of genetic mutations, making phenotypic variation increasingly important. Cancer cells with identical genetic profiles can still exhibit distinct phenotypes, shaped predominantly by dynamic and diverse microenvironmental conditions. Ductal carcinoma in situ (DCIS), an early-stage breast cancer that may remain stable or progress to invasive ductal carcinoma (IDC), exemplifies such environmental variability. At this stage, cancer cells experience fluctuating microenvironmental stresses, including hypoxia, acidosis, nutrient deprivation, and hormonal changes; however, the mechanisms driving this phenotypic diversity remain poorly understood.
Here, we employed an agent-based model (ABM) to simulate cancer cell evolution under different scenarios of temporal environmental fluctuations. Our simulations demonstrated that environmental variability facilitates the sustained coexistence of diverse cancer cell phenotypes through the storage effect. This ecological phenomenon describes that in fluctuating environments, the population maintains diversity by storing species that favor each condition.
We constructed a simplified model in which cells had defined parameters, birth and death probabilities under two distinct environmental conditions, with inherent fitness trade-offs—optimal fitness in one environment resulted in reduced fitness in another. Cell populations, initialized with randomly generated parameters and spatial constraints, were simulated under three environmental scenarios: two constant environments and one periodically fluctuating environment. Populations in constant conditions rapidly evolved towards higher average fitness in the condition they are in, concurrently reducing heterogeneity. In contrast, populations exposed to periodic fluctuations maintained higher levels of heterogeneity despite lower average fitness in both conditions. When these evolved populations were subsequently placed into a randomly fluctuating environment, the population that adapted to periodic fluctuations exhibited superior resilience, maintained higher heterogeneity, and demonstrated greater adaptive potential compared to populations adapted to constant conditions.
Our findings suggest the storage effect can be one mechanism contributing to phenotypic heterogeneity in cancer. This offers valuable insights for developing more effective cancer development and progression models.
Here, we employed an agent-based model (ABM) to simulate cancer cell evolution under different scenarios of temporal environmental fluctuations. Our simulations demonstrated that environmental variability facilitates the sustained coexistence of diverse cancer cell phenotypes through the storage effect. This ecological phenomenon describes that in fluctuating environments, the population maintains diversity by storing species that favor each condition.
We constructed a simplified model in which cells had defined parameters, birth and death probabilities under two distinct environmental conditions, with inherent fitness trade-offs—optimal fitness in one environment resulted in reduced fitness in another. Cell populations, initialized with randomly generated parameters and spatial constraints, were simulated under three environmental scenarios: two constant environments and one periodically fluctuating environment. Populations in constant conditions rapidly evolved towards higher average fitness in the condition they are in, concurrently reducing heterogeneity. In contrast, populations exposed to periodic fluctuations maintained higher levels of heterogeneity despite lower average fitness in both conditions. When these evolved populations were subsequently placed into a randomly fluctuating environment, the population that adapted to periodic fluctuations exhibited superior resilience, maintained higher heterogeneity, and demonstrated greater adaptive potential compared to populations adapted to constant conditions.
Our findings suggest the storage effect can be one mechanism contributing to phenotypic heterogeneity in cancer. This offers valuable insights for developing more effective cancer development and progression models.