Cancer stem cells are proposed to initiate and maintain tumor growth. Deregulation of normal stem cell signaling may lead to the generation of cancer stem cells (CSCs); however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional co-activator YAP1 is a major determinant of CSC properties in non-transformed cells and in esophageal cancer cells by direct upregulation of SOX9. YAP1 regulates the transcription of SOX9 through a conserved TEAD binding site in the SOX9 promoter. Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSCs properties. Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenecity in vivo. The small molecule inhibitor of YAP1, Verteporfin (VP) significantly blocks CSCs properties in cells with high YAP1 and a high proportion of ALDH1+. Our findings identify YAP1 driven SOX9 expression is a critical event in acquisition of CSC properties, suggesting that YAP1 inhibition may offer an effective means of therapeutically targeting the CSC population.

In this large cohort study, a pathCR is confirmed to be associated with better OS and RFS. The presence of a poorly differentiated tumor or SRCs reduces the likelihood of a pathCR. Future research should focus on molecular classifiers. Cancer 2017;123:4106-4113. © 2017 American Cancer Society.

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Despite increases in case complexity, relatively low rates of LR have been maintained while significant improvements in OS have been observed. Further improvements in patient outcomes will likely require disruptive advances in systemic therapy.

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