Hyper-responsiveness of cancer stem cells to microenvironmental cues controls metastasis and therapy response through YAP/TAZ/TEAD

Tang, B.; Minin, J.; Gonzalez, V.; Khan, Z.; Raviv, Y.; Yang, Y.-a.; Carney, C.; Millman, Z.; Grun, D.; Pineda, C. M.; Sharma, A.; Esposito, D.; Yan, H.; Huang, J.; Tran, A. D.; Kruhlak, M.; Yang, H. H.; Lee, M. P.; Wakefield, L. M.

doi:10.1101/2025.03.13.643008

bioRxiv · 10.1101/2025.03.13.643008

Hyper-responsiveness of cancer stem cells to microenvironmental cues controls metastasis and therapy response through YAP/TAZ/TEAD

Tang, B.·Minin, J.·Gonzalez, V.·Khan, Z.·Raviv, Y.·Yang, Y.-a.·Carney, C.·Millman, Z.·Grun, D.·Pineda, C. M.·Sharma, A.·Esposito, D.·Yan, H.·Huang, J.·Tran, A. D.·Kruhlak, M.·Yang, H. H.·Lee, M. P.·Wakefield, L. M.

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Abstract

Cancer stem cells (CSCs) are key drivers of metastasis and therapy resistance but have been challenging to visualize and study in situ. Using a fluorescent CSC reporter, we observed very different population dynamics for CSCs and nonCSCs during metastatic lung colonization in breast cancer models. CSC expansive self-renewal drives early lesion formation before switching to a maintenance mode of balanced self-renewal and differentiation, whereupon nonCSC proliferation takes over as the main driver of metastatic expansion. Mechanistic analyses showed that CSCs are hyper-responsive to microenvironmental cues such as cell crowding and nutrient availability, suggesting a novel role for CSCs as sensors and early responders to fluctuating local conditions in the tumor. Incoming signals converge on YAP/TAZ/TEAD, with heightened CSC sensitivity and response supported by elevated receptor expression and increased chromatin accessibility around enhancers with TEAD binding sites. Targeting inputs to the YAP/TAZ/TEAD node reversed chemotherapy-induced enrichment of CSCs in lung metastases. HighlightsO_LIDifferent population dynamics for breast cancer stem cells (CSCs) and their differentiated progeny in early metastatic colonization C_LIO_LICSCs are hyper-responsive to microenvironmental cues and serve as sensors of local conditions for the tumor C_LIO_LIMany microenvironmental inputs converge on YAP/TAZ to regulate self-renewal vs differentiation fate decisions in the CSC C_LIO_LITargeting YAP/TAZ input pathways blocks chemotherapy-induced enrichment of CSCs C_LI

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Tang, B., Minin, J., Gonzalez, V., Khan, Z., Raviv, Y., Yang, Y.-a., Carney, C., Millman, Z., Grun, D., Pineda, C. M., Sharma, A., Esposito, D., Yan, H., Huang, J., Tran, A. D., Kruhlak, M., Yang, H. H., Lee, M. P., Wakefield, L. M.. 2025-03-15. Hyper-responsiveness of cancer stem cells to microenvironmental cues controls metastasis and therapy response through YAP/TAZ/TEAD. https://doi.org/10.1101/2025.03.13.643008

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