Cooperative adaptation to therapy (CAT) confers resistance in heterogeneous non-small cell lung cancer

by Morgan Craig, Kamran Kaveh, Alec Woosley, Andrew S. Brown, David Goldman, Elliot Eton, Ravindra M. Mehta, Andrew Dhawan, Kazuya Arai, M. Mamunur Rahman, Sidi Chen, Martin A. Nowak, Aaron Goldman Understanding intrinsic and acquired resistance is crucial to overcoming cancer chemotherapy failure. While it is well-established that intratumor, subclonal genetic and phenotypic heterogeneity significantly contribute to resistance, it is not fully understood how tumor sub-clones interact with e ach other to withstand therapy pressure. Here, we report a previously unrecognized behavior in heterogeneous tumors: cooperative adaptation to therapy (CAT), in which cancer cells induce co-resistant phenotypes in neighboring cancer cells when exposed to cancer therapy. Using a CRISPR/Cas9 toolkit w e engineered phenotypically diverse non-small cell lung cancer (NSCLC) cells by conferring mutations in Dicer1, a type III cytoplasmic endoribonuclease involved in small non-coding RNA genesis. We monitored three-dimensional growth dynamics of fluorescently-labeled mutant and/or wild-type cells indi vidually or in co-culture using a substrate-free NanoCulture system under unstimulated or drug pressure conditions. By integrating mathematical modeling with flow cytometry, we characterized the growth patterns of mono- and co-cultures using a mathematical model of intra- and interspecies competitio n. Leveraging the flow cytometry data, we estimated the model’s parameters to reveal that the com...
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research