Cancer cell adaptations along a proliferation-robustness axis drive TME pro-tumor phenotypes

Co-culture of cancer cells with continuously replenished fibroblasts or macrophages drives distinct, recurrent adaptive programs linked to drug tolerance and enhanced tumorigenicity, respectively.

• Why it matters: Tumor microenvironments evolve with cancer cells, but it is unclear which cancer–TME effects reflect adaptive rewiring versus baseline physiological responses.
• What they did: Cancer cells were long-term co-cultured with evolving fibroblasts or macrophages, then the resulting adaptation and response patterns were recapitulated in patient tumors.
• The result: Fibroblast co-culture induced epithelial-mesenchymal transition and increased drug tolerance, whereas macrophage co-culture promoted stress and hypoxia responses and enhanced tumorigenicity, implying a dynamic non-mutational process.

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