Tumor recurrence is an inevitable problem in cancer biology as it varies unpredictably among patients. Surprisingly, our knowledge of tumor recurrence still comes from analyses of post-resistant tumors or single time-point measurements. Critical events during early response that precede resistance and the actual dynamics of drug response in cancer cells is still largely unexplored. The differential sensitivity of melanoma cells has remained puzzling. For instance, why would melanoma cells with the same oncogenic driver (i.e., BRAF-mutations) respond differently to targeted therapies?
In our paper, we coupled experimentation and mathematical modeling to describe diverse dynamics of drug response of multiple melanoma cell lines. We observed that melanoma cell lines under continued MAPK pathway inhibition, regardless of an initial drug response, transitioned into a previously unrecognized non-quiescent state of balanced death and division. We termed this state idling population state. The initial drug responses and time to reach idling population state varied among cell lines. To mathematically formalize these observations, we proposed that cells exist in three distinct states or subpopulations, characterized by their macroscopic proliferation behaviors. These behaviors are E (expanding), S (stationary), and R (regressing), the proportions of which are set the genetic background of the cell. The central assumption of the model is that drug-treatment alters the quasi-potential landscape of cells, and the cells re-equilibrate over the new drug-induced landscape. Therefore, “idling” state is not a property of individual cell types, but rather an emergent property of a drug-treated population as a whole. As such, the idling populations cannot be eradicated by targeting one particular subpopulation (i.e., a basin), but rather the landscape itself must be altered to favor basins for regressing states.
The cover image for the March 27 issue of the Biophysical Journal is an artistic depiction of the distinct epigenetic landscapes that an idling population can exist in to maintain their population size. Here, the four scales represent the balance between distinct phenotypic states and their relative stability. The depth of each basin denotes their stability in a drug-modified epigenetic landscape of melanoma cells. Each state can experience cell death and cell division. The image reflects that with red circles representing dividing cells and dark circles indicating apoptotic cells. This fine balance between cell division and cell death maintains a critical tumor mass, and may effectively model the “residual disease” observed in clinic.
This cover by Rachel Chandler, Biomedical Illustrator at Vanderbilt University, was inspired by the painting The Hallucinogenic Toreador by Salvador Dali. On a macroscopic level, the behaviors of different scales look the same, the state of zero-proliferation. By depicting different configurations for surviving cancer populations, the cover illustrates the complexity of residual disease — often simplified merely as quiescent or senescent cells.
-B. Bishal Paudel, Leonard A Harris, Keisha N. Hardeman, Arwa A. Abugable, Corey E. Hayford, Darren R. Tyson, Vito Quaranta
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