Exploiting cancer stem cells' super-sensitivity to microenvironmental quality to block metastatic progression

Authors

• JA Minin
• B Tang
• VM Gonzalez
• Z Khan
• Y Raviv
• LM Wakefield

Abstract

Cancer stem cells (CSCs) are a minor subpopulation of tumor cells that drive tumorigenesis, metastasis, and resistance to therapy. We have shown that breast CSCs and nonCSCs have very different population kinetics early in metastatic lung colonization. CSCs initially undergo a few expansive self-renewing divisions before plateauing, while the nonCSCs then expand continuously. Live-cell imaging of tumor cell cultures in vitro modeled these population dynamics. Single cell fate mapping showed that CSCs switch from expansive self-renewal to a state of balanced self-renewal and differentiation at a critical cell density. We hypothesized that understanding this switch could lead to more effective targeting of CSCs. We identified several input pathways (including nutrient/growth factor depletion, cell matrix interaction, cell-cell interaction, and inflammation) converging on the YAP/TAZ transcriptional co-regulators that affect CSC self-renewal. The extent to which the individual pathways affect YAP, and subsequently CSC dynamics, depended on the breast cancer model. In all models, CSCs exhibited a more rapid response than nonCSCs to changes in the microenvironment, suggesting that CSCs may serve as sensitive cellular "sensors" of microenvironmental quality for the entire tumor cell population. Targeting the YAP/TAZ/TEAD transcriptional complex directly with a pan-TEAD inhibitor induced differentiation in the CSCs. Combining the pan-TEAD inhibitor, GNE7883, with the chemotherapeutic Paclitaxel reversed the Paclitaxel-induced enrichment of CSCs, resulting in a decrease in both CSCs and nonCSCs. Our data suggest that blocking YAP/TAZ activity directly or via inhibition of upstream inputs may be an effective way to limit CSC-driven metastasis in the clinic.

Scientific Focus Area: Cancer Biology

This page was last updated on Tuesday, August 6, 2024