10th Annual Symposium
Physics of Cancer
September 25-27, 2019
|PoC - Physics of Cancer - Annual Symposium|
Collective motion promotes multi-step drug resistance evolution in dense cellular populations
University of California, Berkeley, Physics Department, Evolutionary Dynamics Group, University of California, Berkeley, USA
One of the most pressing challenges in modern cancer treatment is the evolution of drug resistance. As cancer cell populations proliferate, they can rapidly acquire mutations in their genome, some of which may render their carriers resistant to one or even multiple drugs. Recent work has yielded substantial progress in our understanding of the molecular mechanisms of resistance, revealing that many drug resistance mutations are associated with an inherent fitness cost prior to the onset of treatment. Current models of tumor expansion suggest that, consequently, these slower-growing resistant subclones should be rapidly outcompeted by faster-growing susceptible cells via purifying selection and purged from the population. However, this prediction is in stark contrast to the observed prevalence of drug resistance in the clinic.
Here, using a microbial model system of neoplastic growth, I show that the collective motion inherent to dense cellular populations, including solid tumors, can drastically boost drug resistance evolution. In addition, I present new results advocating for an intricate interplay between such an emergent mechano-cooperation and multi-step adaptation: The prolonged lifetimes of slower-growing resistant lineages substantially increases their potential to acquire subsequent compensatory mutations which alleviate the cost of resistance. This "evolutionary rescue" allows resistant lineages to escape purifying selection indefinitely and, consequently, may lead to treatment failure. Introducing a genetically tailored system of fluorescently trackable "synthetic mutations", tunable in rate and effect, allows us for the first time to quantitatively study evolutionary rescue dynamics from the single-cell scale to the population level. The uncovered mechanisms lay the foundation for a new conceptual framework of intratumoral evolutionary dynamic as an emergent phenomenon, which might crucially inform novel treatment strategies, such as adaptive therapy.