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Despite the rapid progress of targeted cancer therapies, tumors generally develop resistance to treatment. When resistance appears, tumor cells continue to grow unchecked, despite all attempts to slow cancer progression. Although mutations in cancer cells significantly affect drug susceptibility, there is growing recognition that ecological interactions between cells may also play a role.
Jacob Scott, MD, a medical doctor at Cleveland Clinic, wants to find out how cancer cells develop and maintain drug resistance from an eco-evolutionary perspective. He studies the evolutionary strategies that cells use to survive even in the most difficult conditions. His laboratory is particularly interested in the dynamics of sensitive and resistant cancer cells and how they affect the growth of each of them under the selective pressure of cancer treatments.
"Rather than seeking a quick fix to eliminate all resistant cells, which is unlikely, we are working to prevent resistant cells from gaining the upper hand – to" win "every time," says Dr. Scott. "If we can achieve this goal, we can actually make cancer a chronic disease."
Until then, it had been badumed that drug-resistant cells had an advantage of autonomous survival over sensitive cells in the presence of therapy. This means that only the mechanisms intrinsic to the cell promote its survival. The eco-evolutionary perspective, however, recognizes that the growth of cancer cells is partially non-autonomous from cells, it depends both on the proper mechanisms of the cell, but also on other cells and factors in the tumor's microenvironment. Thus, different types of cells can be represented as survival and proliferation "strategies", and the effects of their interactions can be summarized as a "game".
In an article recently published in Nature Ecology and Evolution, Dr. Scott and colleagues develop a first-clbad "gambling test" that allows them to directly quantify and describe the eco-evolutionary interactions between sensitive and resistant tumor cells in an experimental model of non-small lung cancer cells cells sensitive to targeted therapy. This discovery represents a turning point in the relatively young but growing field of evolutionary therapy, which seeks to harness the dynamics that underlie the evolutionary games that cancer cells play. A solid understanding of these games will help fill gaps in understanding how to break the natural trajectory of cancer as it develops drug resistance, in hopes of eliminating it as a "winning" strategy.
"Our motto is" Treat the game, not the player, "said Artem Kaznatcheev, the newspaper's first author and graduate student of Dr. Scott's lab. When cancer cells are targeted directly, the evolution usually acts against the patient. He selects the emergence of resistant cells that allows the tumor to escape therapy and leads to a relapse. To mitigate this risk, Dr. Scott and his team are studying less direct approaches. "We are looking for ways to transform the interactions between cells, that is to say. the games they play – so that we can control their evolution to better help the patient. "
Using a mutant ALK non-small cell lung cancer model that rapidly develops resistance to targeted in vitro therapy, Dr. Scott and his team designed a test to measure and compare the growth rates of sensitive and resistant to alectinib drug when they are grown in different scenarios. . The team discovered that gambling regulates the switching of cancer cells in the presence of drug and tumor-badociated fibroblasts. In a game (called the game "Deadlock"), the resistant cells "always win" and thus develop to form the entire tumor. In another situation (called the "Leader" game), the two types of cells compete and coexist.
In other words, Dr. Scott and his colleagues have actually established that by applying a drug or eliminating fibroblasts, it is actually possible to "cure the game". More studies are needed to explore this as a potential intervention. Among the future areas of study, new trials on other types of cancer should also be applied to expand the growing catalog of games studied by Dr. Scott and his team.
This article has been republished from material provided by the Cleveland Clinic. Note: Content may have changed for length and content. For more information, please contact the cited source.
Reference: Artem Kaznatcheev, et al. Fibroblasts and alectinib tilt the evolutionary games of non-small cell lung cancer. Nature Ecology & Evolution (2019) DOI: https://doi.org/10.1038/s41559-018-0768-z
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