Abstract B19: MYC induces PLD6 to suppress YAP/TAZ-dependent self-renewal of mammary stem cells

Abstract

Abstract For the maintenance of a given tissue it is absolutely critical to balance proliferation and differentiation of stem cells, progenitor cells and terminally differentiated cells. Perturbations of these finely tuned processes can lead to various diseases such as cancer. One factor that has been implicated in the transition from a stem cell to a progenitor/ transit-amplifying cell is the oncogenic transcription factor MYC. Paradoxically, despite its strong pro-tumorigenic capabilities it has been shown to promote differentiation in several tissues such as the skin or the hematopoietic system. To identify critical pathways that might explain MYC's effect on the differentiation of epithelial stem cells we expressed MYC in mammary stem cells. Here, MYC induction led to a drastic reduction in sphere formation indicative of a decreased stem cell potential. Further RNA-Seq and bioinformatical analysis revealed that one of MYC's main functions in mammary stem cells is the repression of YAP/TAZ target genes. YAP and its orthologue TAZ act as nuclear co-activators and are the downstream effectors of the Hippo pathway, a recently discovered pathway with key functions in adult stem cell maintenance and growth control. Using a targeted siRNA screen for MYC target genes we were able to identify a single target gene that is absolutely essential for MYC's ability to repress YAP/TAZ, namely PLD6. PLD6 is a mitochondrial protein that promotes mitochondrial fusion, so that this MYC target gene couples a mitochondrial checkpoint to repression of YAP/TAZ. We were also able to demonstrate the relevance of this pathway in vivo using a mouse that expresses MYC in the mammary stem cell compartment. Interestingly, this pathway is also operational in human breast cancer since a high MYC signature correlates with a low YAP/TAZ signatue in breast cancer patients ultimately leading to a bad prognosis for the respective patient. In summary, we were able to identify a new pathway that couples MYC to mitochondrial biogenesis and the repression of an adult stem cell program. Citation Format: Bjoern von Eyss, Laura Annika Jaenicke, Katrin Wiese, Andreas Rosenwald, Martin Eilers. MYC induces PLD6 to suppress YAP/TAZ-dependent self-renewal of mammary stem cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B19.