Abstract
Tumor clonal heterogeneity drives treatment resistance. But robust models are lacking that permit eavesdropping on the basic interaction network of tumor clones. We developed an in vitro, functional model of clonal cooperation using U87MG glioblastoma cells, which isolates fundamental clonal interactions. In this model pre-labeled clones are co-cultured to track changes in their individual motility, growth, and drug resistance behavior while mixed. This highly reproducible system allowed us to address a new class of fundamental questions about clonal interactions. We demonstrate that (i) a single clone can switch off the motility of the entire multiclonal U87MG cell line in 3D culture, (ii) maintenance of clonal heterogeneity is an intrinsic and influential cancer cell property, where clones coordinate growth rates to protect slow growing clones, and (iii) two drug sensitive clones can develop resistance de novo when cooperating. Furthermore, clonal communication for these specific types of interaction did not require diffusible factors, but appears to depend on cell-cell contact. This model constitutes a straightforward but highly reliable tool for isolating the complex clonal interactions that make up the fundamental “hive mind” of the tumor. It uniquely exposes clonal interactions for future pharmacological and biochemical studies.
Highlights
Intratumor clonal heterogeneity is a critical problem in cancer because it leads to treatment resistance[1,2,3]
We focused on the growth rate phenotype difference to determine whether clones could functionally interact to influence each other’s growth rate, migration, and treatment resistance, irrespective of their individual molecular similarities or differences
Because xenograft tumors are spatially heterogeneous, and xenografts as well as cultured primary tumor cells show an active shift in the clonal landscape during establishment, we investigated basic clonal interactions in the well-established U87MG cell line
Summary
We developed an in vitro, functional model of clonal cooperation using U87MG glioblastoma cells, which isolates fundamental clonal interactions In this model pre-labeled clones are co-cultured to track changes in their individual motility, growth, and drug resistance behavior while mixed. Clonal communication for these specific types of interaction did not require diffusible factors, but appears to depend on cell-cell contact This model constitutes a straightforward but highly reliable tool for isolating the complex clonal interactions that make up the fundamental “hive mind” of the tumor. We purposely chose the well established U87MG cell line, maintained in a homogeneous cell-culture environment, expecting a very stable phenotype of interactions between subclones that is maintained long-term Using this straightforward and highly reliable model, we found a much richer fundamental clonal interaction phenotype than known before
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