Cancer cell adaptations along a proliferation-robustness axis drive TME pro-tumor phenotypes
Abstract
Tumors are highly complex dynamic ecosystems with causal relationships between cancer cells and their tumor microenvironment (TME). To disentangle these interactions, we performed long-term co-culture experiments with cancer cells evolving alongside continuously replenished fibroblasts or macrophages. This allowed us to distinguish between adaptive and physiological responses in specific cancer-TME interactions, which we then also recapitulated in patient tumors. We found that co-culture with fibroblasts induced the epithelial-mesenchymal transition in cancer cells and resulted in their increased drug tolerance, while co-culture with macrophages promoted stress, hypoxia responses and enhanced tumorigenicity. Adaptations were recurrent and partially reversible, but could not be explained by clonal selection, suggesting a dynamic non-mutational process. Moreover, adapted cancer cells elicited cell state changes in the fibroblasts and macrophages consistent with an extended phenotype mode of cancer evolution. Our findings reframe cancer-TME interactions by a systematic dissection according to sets of specific adaptations and programmed responses.
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BibTeX
@misc{pour2026cancer,
title = {{Cancer cell adaptations along a proliferation-robustness axis drive TME pro-tumor phenotypes}},
author = {Maayan Pour and Guisheng Zhao and Angeliki Karatza and Gustavo S. França and Jingye Wang and Linda Procell and Anjali Rao and Deborah A. Corcoran and Ayushi S. Patel and Cristina H. Hajdu and Kwok-Kin Wong and Amanda W. Lund and Edna Cukierman and Itai Yanai},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762245},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762245v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cancer cell adaptations along a proliferation-robustness axis drive TME pro-tumor phenotypes
AU - Maayan Pour
AU - Guisheng Zhao
AU - Angeliki Karatza
AU - Gustavo S. França
AU - Jingye Wang
AU - Linda Procell
AU - Anjali Rao
AU - Deborah A. Corcoran
AU - Ayushi S. Patel
AU - Cristina H. Hajdu
AU - Kwok-Kin Wong
AU - Amanda W. Lund
AU - Edna Cukierman
AU - Itai Yanai
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762245
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762245v1
AB - Tumors are highly complex dynamic ecosystems with causal relationships between cancer cells and their tumor microenvironment (TME). To disentangle these interactions, we performed long-term co-culture experiments with cancer cells evolving alongside continuously replenished fibroblasts or macrophages. This allowed us to distinguish between adaptive and physiological responses in specific cancer-TME interactions, which we then also recapitulated in patient tumors. We found that co-culture with fibroblasts induced the epithelial-mesenchymal transition in cancer cells and resulted in their increased drug tolerance, while co-culture with macrophages promoted stress, hypoxia responses and enhanced tumorigenicity. Adaptations were recurrent and partially reversible, but could not be explained by clonal selection, suggesting a dynamic non-mutational process. Moreover, adapted cancer cells elicited cell state changes in the fibroblasts and macrophages consistent with an extended phenotype mode of cancer evolution. Our findings reframe cancer-TME interactions by a systematic dissection according to sets of specific adaptations and programmed responses.
SN - 2692-8205
ER -