The development of treatment resistance is one of the key challenges in modern cancer and antibiotic therapy. New therapeutic approaches aim to curb the spread of resistance through the targeted timing of treatment cycles. Researchers at the Max-Planck-Zentrum für Physik und Medizin (MPZPM) have now demonstrated how a deeper understanding of the physical processes occurring in growing tumors and microbial biofilms can contribute to the success of “evolution-based” therapies.
Solid tumors and microbial biofilms consist of densely packed cells. Nutrients, oxygen, and other resources essential for growth decrease from the periphery of the cell population toward the center. This declining supply of resources regulates cell growth. Resistant cells that arise deep within a population are restricted in their growth and can spread only slowly. Treatment fundamentally alters this situation, sometimes with serious consequences for the course of therapy. An interdisciplinary team of scientists led by Dr. Jona Kayser, head of the Emmy Noether Research Group “Cellular Evolution” at MPZPM, is investigating how fundamental biophysical processes influence the emergence and development of resistance in dense cell aggregates. Their new study in Nature Ecology & Evolution shows that physical processes play a decisive role in determining the optimal timing of treatment cycles.
The team combines microbial model systems and computer simulations to observe the “evolution” of resistance and decipher the underlying mechanisms. “We use a ‘Real-To-Sim-To-Real’ approach. In this approach, therapy-mimicking experiments with genetically modified yeast cells serve as the basis for digital twins. The therapeutic strategies optimized on the computer are subsequently tested in experiments,” says Nico Appold, one of the two lead authors.
Using this approach, the researchers were able to show how the physical coupling of environmental and growth dynamics divided treatment outcomes into two distinct classes. The “sweet spot” – the range of optimal therapeutic efficacy – is located precisely at their boundary.
“Our results show that even small changes in treatment timing can determine the success of therapy,” says Timon Citak, the other lead author.
The study shows that treatment not only directly affects cells but also indirectly influences their environment, and that the two interact. For evolutionary therapeutic approaches, therefore, in addition to the overall size of a tumor, how and where cells regrow during treatment breaks could also be important.
“Our findings are fundamental in nature and reveal underlying mechanisms. They cannot be applied to the treatment of patients yet, but in the long term, this physical understanding could be crucial to the success of future treatment strategies,” emphasizes Kayser, group leader and corresponding author of the study. “In the next step, we want to investigate whether similar physical mechanisms also occur in more realistic model systems, such as three-dimensional tumor organoids.”
Nature Ecology & Evolution
Experimental study
Cells
A microbial therapy-mimicry assay shows how spatial resource dynamics control resistance escape